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Introduction

The first patient with severe acute respiratory syndrome (SARS) in Taiwan was recognized on March 14, 2003 at National Taiwan University Hospital (NTUH). Thereafter, there were 170 patients with the final diagnosis of probable SARS visiting NTUH for medical help till the ending of SARS epidemic in Taiwan. Among the 170 patients, 79 patients received their treatments for SARS at NTUH and others were transferred to other hospitals. Of the 79 patients, 17 had complicated underlying diseases, which made their presentations of SARS be atypical, with the severity classified as ultimately or rapid fatal according the McCabe criteria. The clinical manifestations of the other 62 patients were typical for SARS. Here we describe the clinical manifestations, treatment outcome, and predictive factor for mortality of the 62 patients.

Treatment protocol for SARS at NTUH

Oral ribavirin was used soon after establishing the diagnosis of SARS with a loading dose of 2000 mg followed by 1200 mg per day if the body weight was over 75 kilogram or 1000 mg per day if the body weight was less than 75 kilograms. The duration was 10 days unless the patient developed adverse effects. Antimicrobial agents for community-acquired pneumonia, either moxifloxacin alone or ceftriaxone plus azithromycin, were also administered at the same time. Methylprednisolone was usually administered in the second week of the disease course if the patient developed a flare of fever, progressed clinical symptoms (such as dyspnea or diarrhea), a surge or re-surge of CRP level, or rapid deterioration of chest radiographic findings (development of new infiltration). It was indicated in the first week of disease course only if there were very rapidly progressed clinical symptoms or laboratory abnormalities, such as elevated CK, LDH, CRP, and the progression of chest radiographic findings. The dosage of methylprednisolone was 2 mg/kg/day for five days and then it was tapered off. Pulse therapy with methylprednisolone 500 mg/day for three days was used if there was a significant disease progress under the standard regimen. Intravenous immunoglobulin (IVIG) was administrated while existence of severe leukopenia (< 2 X 109/L) and/or thrombocytopenia (< 100 X 109/L), or if there was a marked local progression of lesions on chest radiography in the first week of disease course. The dosage of IVIG was 1 gm/kg/day for two days. Once patients were intubated and supported by a mechanical ventilator, respiratory care according to the principles suggested for managing acute respiratory distress syndrome was applied.

The rationale to use steroid in the second week of disease course based on the following two evidences: First, as our experience to treat the first six patients with probable SARS, early use of steroid, in the first week of disease course, did not prevent the subsequent exacerbation of respiratory distress. Second, Pieris et al demonstrated that the viral loads of SARS-CoV in SARS patient were peaking on day 10 after disease onset and they proposed that the early symptoms in week 1 of disease might be largely related to the effect of viral replication and the so called "subsequent deterioration" in week 2 of disease might be due to the host immune response rather than uncontrolled viral replication.

The rationale to use IVIG in SARS patients with severe cytopenia was based on the findings of bone marrow study of the second SARS patient at NTUH, which demonstrated evidence of haemophagocytosis.

Demographic data of the 62 patients

The male to female ratio was 24/38. Their age ranged from 24 to 70 years, with the median of 46.5 years. Only 10 of them had mild underlying diseases, which were classified as non-fatal according to the McCabe criteria.

Presenting symptoms

The presenting symptoms of the 62 patients were listed in following table.

Laboratory data at presentation

The abnormal laboratory data at presentation of the 62 patients were described in following two tables. At presentation, hemogram, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), C-reactive protein (CRP) levels were only available in 62, 58, 38, 16, 55, and 57 patients, respectively.

Abnormalities in Chest Radiography (CXR)

At presentation, 47 of 62 (75.8%) patients had abnormalities in their CXR. However, all 62 patients developed abnormalities in CXR during their hospitalizations. The duration from disease onset to appearance of abnormality in CXR ranged from 1 to 12 days, with the median of 4 days. Most patients presents with single lobe pneumonia in CXR (72.6%).

Course during Hospitalization

Respiratory distress developed in 88.7% patients, with the most severe day happened on the 10th hospitalized day (10±2.7 days). Diarrhea exacerbated in 41.9% patients after admission, with the most severe day on the 9th hospitalized day (9.7±4.7days).

As to laboratory findings during the course of hospitalization, leukopenia (2499±691/μl) was observed in 59.7% patients, especially lymphopenia (619±281/μl) in 93.5% patients, on the 7th hospitalized day (7.6±2.4, 7.4±2.2 respectively). Throbocytopenia (105.8±30 K/μl) was noted, too, in 80.6% patients on the 7th hospitalized day (7.0±2 days).

Abnormal liver function observed with elevated AST(133.5±291.6) and ALT (111.4±139.8) in 88.7% and 82.3% patients. The most severe day happened on 10.6±4 and 14.4 ±4.1 days respectively. LDH (1264.6±1465.6) elevation noted in 80.6% patients with the most severe day on 10.9±3.8th day of hospitalization. CK (5925.9±4311) elevated in 43.5% patients with the most severe day on the 7.9±4.2th day of hospitalization. CRP (6.7±4.1) elevation noted in 91.9% patients with the most severe day on the 9.1±2.7th day of hospitalization.

83.9% patients developed new pneumonia patch during hospitalization with the most severe day on 10.2±2.7 day.

Laboratory Evidence for SARS

Throat swab rt-PCR and anti-SARS antibody seroconversion were used as evidence for SARS. Throat swab rt-PCR was positive in 18/62 patients (29.0%). Seroconversion for SARS-CoV was observed in 41/43 (95.3%) patients. The data of the other 19 patients were not available. As to the other suspected SARS patients (18/62, 29.0%), there was no microbiologic or serologic support.

Special Treatment: IVIG

38 patients received IVIG. 22 of these patients received IVIG under the indication of cytopenia and the other 16 patients under the indication of marked local progression in the first week of disease. For the 22 patients using IVIG with the indication of severe cytopenia, the WBC counts before and after IVIG were 2612 1173 vs 4298 2809 / L (P=0.014); and the Platelet counts before and after IVIG were 104 35 vs 141 46 K/ L (P=0.002).

Treatment Outcome

The median follow-up days for these patients were 42 days with range from 4 to 107 days. The mortality rate was 6.5% (4/62). Complications noted in 15/62 patients (24.2%), including lung fibrosis (8.1%) , rhabdomyolysis(4.8%), peripheral neuropathy (8.1%), and acute renal failure: 3 (4.8%). Nosocomial infections, including catheter related infection with Candida parapsilosis 1 (1.6%) and bacterial infections with MRSA: 1 (1.6%); MRSE: 1 (1.6%); enterococci: 2 (3.2%)oA. baumannii: 2 (3.2%); K. pneumoniae: 1 (1.6%); S. marcescense: 1 (1.6%) were noted.

Risk Factors for Mortality

Risk factors for mortality was analyzed with univariate analysis which revealed initial CRP level, initial lymphocyte count, peak LDH level were associated with mortality. But multivariate analysis revealed initial CRP level was the only significant predictor for mortality (P=0.006, OR=1.59). As to risk factors for respiratory failure, Initial CRP, age, initial ANC, initial lymphocyte count, peak CRP level, peak LDH & CK level were associated with respiratory failure according to univariate analysis. But multivariate analysis revealed only peak CRP level was associated the respiratory failure (P=0.002, OR=1.52).

Summary

After all the terrible spray of SARS and tensed situation we had encountered in 2003, clinical data and experience had been collected in Hong Kong, Canada and Taiwan. The diagnosis criteria for SARS had been adjusted according to these new information and treatment protocol for SARS had been widely discussed. These will help us to intervene further possible outbreak of SARS or other emerging new infection diseases in the future.