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1Departments of Respiratory Disease and Laboratory Medicine, First Municipal People's Hospital of Guangzhou, 1 Panfu Road, Guangzhou, People's Republic of China 2Eighth Municipal People's Hospital of Guangzhou, 627 Dongfeng Dong Road, Guangzhou, 510180, People's Republic of China 3Second Affiliated Hospital of Guangzhou Medical College, 250 Changgang Dong Road, Guangzhou, 510655, People's Republic of China 4Guangzhou Red-Cross Hospital, 396 Tongfu Zhong Road, Guangzhou, 510220, China 5Sixth Municipal People's Hospital of Guangzhou, 19 Yuanchu Xijie, Tianhe Guangzhou, 510260, People's Republic of China 6Division of Immunity and Infection, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Correspondence Z. Zhao zhaozw1963{at}yahoo.com.cn
Received May 22, 2003
Accepted June 11, 2003
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Abstract |
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 TOP Abstract INTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgementsREFERENCES |
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INTRODUCTION |
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TOPAbstractINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgementsREFERENCES |
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We describe here the clinical features and epidemiology of the Guangzhou outbreak, together with results of a randomized treatment trial in 190 patients with presumed SARS.
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METHODS |
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The index patient for the Guangzhou outbreak was a 46-year-old male fish merchant who travelled to Zhongshan city, where the first recorded outbreak of SARS was occurring, during the middle of January 2003. He denied any close contact with SARS-infected patients and never went to the local hospitals there. On 26 January 2003, the patient attended the local clinic in Guangzhou after the onset of fever (later investigation found no medical staff were infected in that clinic). He was transferred to the respiratory department of the Second Affiliated Hospital of Sun Yet-San Medical University, Guangzhou, on 30 January 2003 because of worsening dyspnoea and then transferred to the Third Affiliated Hospital of the same medical university on 1 February 2003. He deteriorated further due to the onset of adult respiratory distress syndrome (ARDS) and was ventilated, being transferred to the Eighth Municipal People's Hospital of Guangzhou on 8 February 2003. He recovered from a critical condition after symptomatic treatment and was discharged from hospital after 30 days of hospitalization with partial pulmonary fibrosis.
While the patient was hospitalized in the Second Affiliated Hospital for 2 days, he infected 28 medical staff in the respiratory department (located on the 12th floor) of that hospital, including the ambulance driver who transferred him to the Third Affiliated Hospital. The driver died of SARS 2 weeks later, his wife being infected as well. The outbreak spread rapidly from the respiratory ward, which is located on the 12th floor, to the 13th and 15th floors on the same building; in all, a further 65 medical and nursing staff were affected, as well as 10 in-patients. These floors shared the same central air-conditioning system. A total of 23 medical staff became infected in the Third Affiliated Hospital. Between 30 January and 9 February 2003, 18 individuals became infected after visiting patients, among them the parents-in-law of the index patient, who both died of SARS. Four medical staff who intubated the index patient in the Third Affiliated Hospital of Sun Yet-San Medical University became infected from the index patient. The time-course for the index patient is shown in Fig. 2. The disease spread in family groups, but not all were infected within a group. There was no evidence of a community outbreak of the disease except amongst those living with or visiting infected patients. In excess of 200 patients were identified as probable SARS cases and 190 patients fulfilling the criteria (Table 1) were allocated randomly to one of four treatment protocols.
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Definitions.
The Guangdong prophylaxis and treatment group for atypical pneumonia produced a working case definition (Table 1). A total of 120 cases satisfy all five criteria and the other 70 cases satisfy criteria 2–5. With regard to criterion (2), subcriteria (i) and (iii) had to be present for criterion (2) to be positive.
Patients with pneumonia of bacterial or fungal aetiology confirmed by laboratory investigation were excluded. Patients with lung neoplasm, non-inflammatory pulmonary interstitial diseases, pulmonary oedema and atelectasis, pulmonary thrombosis, eosinophilic pneumonitis or pulmonary vasculitis were also excluded.
ARDS was defined according to accepted criteria (Bernard et al., 1994).
Case selection.
A total of 190 infected patients who satisfied the case definition were included in the treatment study. There were 70 males and 120 females, aged 16–84 years (mean 28.6 ± 10.3). Of these, 60 cases were medical staff, who had been infected with an apparent incubation period of 2–15 days following contact with symptomatic patients (mean incubation period 3 ± 4 days).
Laboratory investigations.
Bacterial cultures of throat swabs and sputum were carried out. Serological detection of antibodies for influenza A and B in 120 patients was undertaken; in addition, 60 patients were tested for antibodies to H5N1 using an ELISA method in the laboratories of the Guangdong Centre for Disease Control. Sera from 60 patients were checked for antibodies to mycoplasma, chlamydia, legionella, adenovirus, coxsackievirus, respiratory syncytial virus (RSV) and cytomegalovirus (CMV).
Treatment We distributed all patients admitted between 2 and 14 February 2003 randomly to groups A, B and C. After 14 February, the next 60 patients were allocated to group D. Although age, sex and severity were not formally controlled, inspection of the patient records revealed the groups to be broadly the same.
Group A.
Forty cases, treated routinely with ribavirin i.v. 0.4–0.6 g day-1 and cefoperazone/sulbactam 2.0 g b.i.d., oxygen by mask 3–5 l min-1. Those patients with a blood oxygen saturation (SaO2) < 92 % were supported with non-invasive continuous positive airway pressure (CPAP). If CPAP failed (SaO2 < 90 %), mechanical ventilation was used by tracheal intubation.
Group B.
Thirty cases, treated with a fluoroquinolone plus azithromycin i.v. 0.4 g day-1, combined with recombinant interferon-
(IFN-) i.m. 3 000 000 U day-1 and restricted use of steroids. Groups A and B received no steroids during the first 14 days of treatment. If steroids were subsequently used, the dose of methyl prednisolone was 80–160 mg day-1. Indications for mechanical ventilation were the same as for group A.
Group C.
Sixty cases, treated with a quinolone plus azithromycin i.v. 0.4 g day-1. Some patients were given recombinant IFN- i.m. 3 000 000 U day-1. Steroids were added (methyl prednisolone 80–160 mg day-1 for 2–3 days) when symptoms worsened or pulmonary infiltrates increased. Indications for mechanical ventilation were the same as for group A.
Group D.
Sixty cases, treated with levofloxacin 0.2 g b.i.d. plus azithromycin 0.6 g day-1 i.v. drip. Forty-five patients were given recombinant IFN- i.m. 3 000 000 U day-1. If patients failed to respond (continuing high fever), with pulmonary infiltrates involving more than one pulmonary segment or expanding area of consolidation, they were treated with high-dose methyl prednisolone for 5–14 days (160–1000 mg day-1 depending on symptoms and X-ray results). Oxygen 3–5 l min-1 was given by mask if SaO2 < 95 % or, if patients felt short of breath, non-invasive CPAP was used. If CPAP failed (SaO2 < 90 %), mechanical ventilation was used.
Patients were treated with appropriate broad-spectrum antibiotics if a bacterial infection was confirmed by culture. Immunoglobulins, thymic peptides or recombinant human thymus proteins were given to 120 critically ill patients in all groups. Patients who had a normal temperature for 7 days after withdrawal of steroid with resolution of pulmonary infiltrates were discharged home.
Histopathology.
Needle biopsy of lung was only performed in those cases that died (post-mortem).
Statistical analysis.
SPSS 8.0 software for differential analysis and 
2 test were used.
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RESULTS |
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Chest X-ray findings
Most patients had a normal X-ray at onset of fever and progressed to interstitial changes or speckled/patchy exudates within 1 week. These involved unilateral or bilateral lung fields becoming larger patchy exudates in 2–3 days with exacerbation of shortness of breath. Of the cases, 23 had infiltrates localized in one pulmonary segment (12 %), 26 localized in one lobe (13.7 %), 32 cases had signs in one pulmonary field (16.8 %) and 93 cases involved both lungs (48.9 %). Diffuse damage was seen in 36 cases; 16 cases only showed interstitial changes.
Laboratory findings
On admission, white blood cell counts of 4.0–10 x 109 l-1 were found in 144 cases, < 4.0 x 109 l-1 in 46 cases and < 2.0 x 109 l-1 in 26 cases. Platelets were < 10 x 1012 l-1 in 25 cases (13.2 %), with one case of 2.5 x 1012 l-1. One case had neutropenia, lymphopenia and thrombocytopenia. Elevated levels of glutamate pyruvate transaminase (GPT) and glutamate oxaloacetate transaminase (GOT) (normal range < 40 U l-1 for both tests) were seen in 126 cases, with the highest up to 500 U l-1, mean 94 ± 12 U l-1; 50 cases had elevated levels of lactate dehydrogenase (LDH) and creatine phosphokinase (CPK). Some 95 cases were seriously ill, with pulmonary infiltrates involving more than two lobes and a significant decrease in T lymphocyte subgroups, especially affecting CD4+, with levels of only 0.03 x 109 l-1, mean 0.085 ± 0.02 x 109 l-1, which comprised 10–20 % of total T lymphocytes (normal value is 24–40 %), giving a CD4+/CD8+ ratio of < 1.
Bacterial cultures of sputum yielded no significant pathogens. Cultures for Mycoplasma spp. from nasopharyngeal secretions or sputum in 46 cases were also negative. Serum antibody tests for adenovirus, coxsackievirus, RSV and CMV all failed to demonstrate an acute infection. Sera tested for influenza A and B, influenza A and (H5N1) all failed to demonstrate an acute infection. Sixty cases tested using ELISA for the detection of mycoplasma, chlamydia and legionella antibodies detected 10 positive sera at 1 : 80 dilution, but no increase was seen in paired sera. In addition, 20 patients initially suspected of SARS in whom second sera showed a fourfold increase in antibodies to one of the pathogens after 1 week of onset, and also responded well to at least 3 days of treatment with a quinolone plus azithromycin, were excluded from the study cohort of 190 patients. These patients were also found to lack a history of close contact with known cases.
Treatment group outcomes
The responses of the four treatment groups are summarized in Table 3. Patients admitted in the early stages of the outbreak were treated using the group A protocol. All the cases had no early resolution of pyrexia. Within 7–10 days, most of the patients had pulmonary infiltrates and increased shortness of breath. Twelve of the 40 cases had SaO2 < 92 % and PaO2 < 90 mmHg and needed CPAP; of them, three received mechanical ventilation and two died of severe ARDS. After a change of the regimen to the use of quinolone and azitromycin as well as methyl prednisolone 80–160 mg day-1, the rest of the group A patients had resolution of fever at day 10–14, together with improvement in respiratory symptoms and SaO2.
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The 30 patients in group B had little reduction in temperature until day 10–16, eight cases needed CPAP and two cases received mechanical ventilation, but there were only two deaths. After adding methyl prednisolone 80–160 mg day-1 into the therapy, the remaining group B patients improved within 3–5 days and were discharged after 20–30 days of illness. The 60 patients in group C also failed to show temperature reduction and improvement in respiratory symptoms until methyl prednisolone was administered. Of them, 20 cases needed CPAP; eight of these 20 received mechanical ventilation and required an increased dose of methyl prednisolone from 480–1000 mg day-1. Two of the eight cases improved. Seven of 60 cases in group C died of severe ARDS.
The 60 cases in group D were treated with methyl prednisolone if fever did not resolve within 3 days. Dosage for the steroid was chosen according to the area of pulmonary infiltrates: 160 mg day-1 if one lobe was involved, 320 mg day-1 if more than one lobe was involved. A substantial proportion of cases (36/60) had temperature resolution within 1–3 days after starting treatment. Fifteen of 60 needed an increased dosage of the steroid from 160 to 320–720 mg day-1 to maintain respiratory physiological parameters and to control temperature. None of the group D patients needed mechanical ventilation and all of them recovered and were discharged from the hospital.
Follow-up
Side effects of the steroid were minimal, as methyl prednisolone was used in combination with Omelazone 40 mg b.i.d., i.v. during treatment. No case had upper gastrointestinal tract bleeding. One case developed oral candidiasis and elevation of plasma glucose. No rebound phenomena were experienced during sudden withdrawal of the steroid either after 5–14 days of clinical use or after a two-stage dosage reduction protocol.
Most of the discharged patients still had palpitation and shortness of breath within the first week, especially those with incomplete resolution of pulmonary infiltrates. In most cases, continuing use of methyl prednisolone 40–80 mg day-1 for 1 week helped to relieve the symptoms.
Histopathology
Eleven of the 190 patients died, all of ARDS, four females and seven males. Eight cases were >70 years old, the remaining cases being 36, 40 and 45 years old. Three of the dead patients had needle biopsies of the lung performed. Inflammatory infiltration was found in interstitial tissue of the lung. Congestion with dilation, bleeding and deformation of capillaries was seen. Exfoliations of the pulmonary alveolar epithelia were extensive. Hyaline changes in some pulmonary alveoli were noted with proliferation and fibrosis of connective tissue in the pulmonary alveolar interstitial space.
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DISCUSSION |
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TOPAbstractINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgementsREFERENCES |
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The striking features of this outbreak of SARS were: (i) a highly contagious pneumonia spread mainly through close contact, unlike influenza, which predominately causes outbreaks in the community; (ii) presentation with fever, usually of sudden onset; (iii) no obvious respiratory symptoms such as cough, shortness of breath or chest X-ray changes at the beginning of the infection, with little or no sputum produced. The patients deteriorated rapidly after 3–7 days of illness, with exacerbation of shortness of breath and increase of lung infiltrates, usually bilateral. In our experience, if not treated early, some patients easily developed ARDS, especially older patients. Early use of high-dose steroids appeared to help recovery from SARS. Some patients were left with pulmonary fibrosis after recovery. This outbreak was reminiscent of the outbreak of influenza type H5N1 in Hong Kong in 1997, when 18 patients were infected and six of them died of ARDS (Chan, 2002; Yuen et al., 1998). The difference between these two outbreaks is that there was no person-to-person transmission in the H5N1 outbreak.
Comparing the clinical outcomes of the different therapies, the group D therapy gave the best results. This favourable outcome may have been influenced by inconsistencies in the number of patients in each group given CPAP ventilation. No particular advantage in using ribavirin was seen; this contrasts with the advantages we found in the early use of steroids and non-invasive respiratory support. This approach reflects the opinion expressed by workers treating patients in Canada (Poutanen et al., 2003), who suggested adopting a lung-protective strategy for ventilation. The disease did not respond to antibiotic treatment, and the combined use of interferon and large dose of immunoglobulins had no obvious effect. The early use of high-dose steroids in combination with a quinolone plus azithromycin gave the best outcome, with improvement of clinical symptoms and signs, a decreased incidence of ARDS and mechanical ventilation as well as mortality. The steroids may help by reducing the damaging effect of the local inflammatory response (Peers & Flower, 1990; Williams & Yarwood, 1990). We chose a quinolone plus azithromycin as the baseline regimen for treating atypical pneumonia and applied it to this outbreak. Although the coronavirus would not be sensitive, there may have been a protective effect on the development of secondary infections. Another important finding is that most patients, especially young patients, responded well to non-invasive nasal CPAP, which the patients received when (i) respiration rate was >30 times min-1, (ii) SaO2 was < 95 % or (iii) patients developed respiratory distress. CPAP was carried out with an air pressure of 5–15 cm H2O and was not discontinued for more than 15 min at a time. If patients failed on CPAP (SaO2 < 90 %), or were intolerant of CPAP, they were intubated and ventilated using CPAP or positive end-expiratory pressure (PEEP).
At the First Municipal People's Hospital of Guangzhou, the following cross-infection precautions were taken for medical and nursing staff. Two isolation gowns were worn, one over the other, and two 12-layer cotton-yarn face masks were worn for all contact with patients. A face visor was also worn before undertaking intubation and sputum aspiration. Gloves were worn at all times and changed frequently. Patients were nursed in either two- or four-bedded rooms, and completely separate areas were provided for the medical staff office and rest area on a different floor of the building. The wards used natural ventilation instead of the central air-conditioning system. By using these precautions, no cases of transmission to the medical and nursing staff of this hospital occurred during the outbreak.
This series represents the largest and earliest group of SARS patients treated so far; previously, 138 patients in Hong Kong were described (Lee et al., 2003). Our clinical and laboratory findings are very similar to those and other, much smaller published series. This paper summarizes our experience up to 10 March 2003. During the last month (to 23 April 2003), there have been 160 more new cases of SARS admitted to our hospitals, aged between 16 and 89. All of them have been treated with the group D protocol; 135 of them have now been discharged, and three patients died (aged 89, 76 and 53). The combined mortality for the 350 treated cases has been 4 %. At the time of writing, the SARS outbreak in Guangzhou is under control, with an incidence of new cases of 1–2 day-1. Because the response of different groups of patients to different therapeutic regimens has been documented, we are able to suggest that the early and aggressive use of steroids combined with non-invasive ventilatory support should offer the best hope for a favourable outcome. Until more antiviral and vaccine protection becomes available, optimizing supportive therapy is crucial to reducing mortality from SARS.
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Acknowledgements |
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TOPAbstractINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgementsREFERENCES |
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TOPAbstractINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgementsREFERENCES |
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