Case Report An Indolent Case of Severe Acute Respiratory Syndrome Man-Fai Lam, Gaik C. Ooi, Bing Lam, James C. Ho, Wing H. Seto, Pak L. Ho, Poon C. Wong, Raymond Liang, Wah K. Lam, and Kenneth W. Tsang University Departments of Medicine, Diagnostic Radiology, and Microbiology, University of Hong Kong, Queen Mary Hospital, Hong Kong, China
Severe acute respiratory syndrome (SARS) is a highly contagious and typically rapidly progressive form of atypical pneumonia, which spread from Asia to many parts of the world in early 2003. Clinical diagnosis of SARS requires the presence of unremitting fever and progressive pneumonia despite antibiotic therapy, particularly in the presence of lymphopenia and raised transaminase levels. We report the case of a woman who had undergone a successful allogeneic bone marrow transplant for acute myeloid leukemia. She presented initially with fever and a normal chest radiograph. Her indolent clinical course of SARS was punctuated by resolution of fever, but there was progressive radiologic deterioration and increasing serum antibody titer against SARS coronavirus. Treatment with oral prednisolone and ribavirin normalized her lymphopenia, altered transaminases, chest radiograph and high-resolution computed tomography appearances rapidly. Our experience should alert other clinicians in recognizing this atypical indolent presentation of SARS, to protect health care workers and the community at large and to ensure that these patients are properly treated. Keywords: severe acute respiratory syndrome; bone marrow transplantation; clinical presentation
Severe acute respiratory syndrome (SARS) is a highly contagious disease caused by a novel coronavirus (SARS-CoV), which has to date caused 813 deaths and 8,437 cases in 30 countries worldwide. According to the updated World Health Organization and the CDC diagnostic criteria for SARS, patients should fulfill clinical, epidemiologic, and laboratory criteria. Patients usually present with fever (temperature ⬎ 38⬚C for over 24 hour), chills, dry cough, dyspnea, malaise, headache, and only mild respiratory illness in the initial phase, but this is usually followed by progressive pneumonia, which could deteriorate into acute respiratory distress syndrome (ARDS) (1–3). The epidemiologic criteria include a recent travel history to the epidemic area or having a close contact within 10 days of onset of symptoms with patients with or suspected of having SARS. Laboratory evidences for SARS-CoV infection, namely rising titer of anti–SARS-CoV antibody, reverse transcriptase–polymerase chain reaction detection of SARS-CoV RNA, and isolation of the virus, are not strictly needed to diagnose SARS as the syndrome was defined before the novel SARS-CoV was
(Received in original form June 6, 2003; accepted in final form September 5, 2003) Supported by a SARS Research Grant of the University of Hong Kong. Correspondence and requests for reprints should be addressed to Kenneth W. Tsang, M.D., FRCP, Associate Professor and Honorary Consultant Physician, Division of Respiratory and Critical Care Medicine, University Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China. E-mail:
[email protected] Am J Respir Crit Care Med Vol 169. pp 125–128, 2004 DOI: 10.1164/rccm.200306-754CR Internet address: www.atsjournals.org
actually discovered (2, 3). Nevertheless, anti–SARS-CoV IgG has recently been reported to be positive in over 90% of patients with SARS and is increasingly being recognized as an important diagnostic test (4). Although the vast majority of patients with SARS display fever, radiographic consolidation, lymphopenia, and altered transaminase levels at initial presentation, clinical diagnosis of SARS usually requires the presence of unremitting fever and progressive pneumonia despite antibiotic therapy. As there is no validated rapid diagnostic laboratory test, SARS is very difficult to diagnose in the early stages when the chest radiograph is still normal, even in the presence of fever. Here, we report the case of a patient with an indolent presentation of SARSCoV infection. Our experience should help alert other clinicians in recognizing this mode of presentation of SARS-CoV infection, which could still be as highly contagious. Recognition of this indolent form of SARS is important to protect health care workers and the community at large and to ensure that these patients are properly dealt with.
CASE REPORT A 45-year-old housewife was admitted into Queen Mary Hospital, a regional teaching hospital, on March 17, 2003. She reported a 1-day history of fever, chills, and malaise. She did not have any respiratory symptoms including cough, dyspnea, or limitation of exercise tolerance. She had a known history of acute myeloid leukemia for 2 years with successful allogenic bone marrow transplantation performed in September 2001. After transplantation, the marrow regenerated well. Cyclosporin A and cotrimoxazole (weekly) were stopped in January 2003, as she was considered to be in complete remission. Her leukocyte and lymphocyte counts were 4.8 (4–11) and 1.6 (1.5–4.0) ⫻ 109/L respectively, and her liver function indices were normal in January 2003. At a routine follow-up on March 6, 2003, her alanine aminotransferase and asparate aminotransferase were incidentally found to be 44 (5–31 U/L) and 32 (12–28 U/L) although she was asymptomatic. This was attributed to liver-specific graft-versus-host disease, as no other systems appeared to be involved. Azathioprine 25 mg daily was commenced from March 6, 2003, and was stopped on the day of admission. However, there was no history of close contact with persons with respiratory symptoms, or any travel history to SARSendemic areas in the last 6 months. On admission, physical examination revealed a temperature of 38⬚C but no evidence of lymphadenopathy or physical signs suggestive of recurrence of leukemia. Detailed systemic examination revealed no abnormalities in the respiratory, cardiovascular, or abdominal systems. After full septic work-up, intravenous cefepime 1 g three times a day was commenced. Her leukocyte count was normal (5.8 ⫻ 109/L), although she had lymphopenia (0.9 ⫻ 109/L), and her alanine aminotransferase and asparate aminotransferase continued to be marginally abnormal (32 and 30 U/L, re-
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spectively). Her chest radiograph showed clear lung fields (Figure 1A). After admission, she continued to have persistent swinging fever (38–39⬚C), and repeated septic work-up did not reveal any foci of infection. Her nasopharyngeal aspirate and sputum were negative for respiratory virus (including influenza A, B, parainfluenza, and respiratory syncytial virus), and sputum for acidfast bacilli, bacteria, and fungus. She was, therefore, switched to intravenous imipenem and cilastatin 500 mg four times a day on Day 6. On Day 9 after admission, despite being clinically stable, a repeat chest radiograph showed mild bilateral infiltration in the lower zones, and clarithromycin 500 mg twice a day was added to her treatment. Her fever suddenly subsided on Day 11, although her serial chest radiograph showed progressive deterioration. This showed maximal bilateral lower zone infiltration on Day 14 (Figure 1B). High-resolution computed tomography of thorax was performed, and it showed patchy consolidation in the right lower lobe with air bronchograms (Figure 2A) and multicentric subpleural ground glass opacification in the both lower lobes and the right middle lobe. None of the microbiologic cultures yielded any pathogenic bacteria, acid-fast bacilli, or fungus in her blood, sputum, or urine specimens. The rapid viral antigens detection was negative, and the serologic titres of Chlamydia pneumoniae, Chlamydia psittaci, Mycoplasma pneumoniae, and Legionella pneumophilia were not increased. However, reverse transcriptase–polymerase chain reaction of the nasopharyngeal aspirate was positive for SARS-CoV, and IgG titers increased from 1/160 (Day 7) to 1/ 2,560 (Day 14) (4). Although she had no further fever, she continued to suffer from lymphopenia, malaise, and dry cough. Oral prednisolone (1 mg/kg) and ribavirin (2,400 mg/day) were commenced on Day 14. The patient’s liver function indices and lymphopenia normalized within 2 and 3 days afterwards. Serial chest radiographs showed rapid resolution of bilateral lowerzone infiltration, and a repeat high-resolution computed tomography showed no significant residual disease on Day 21 (Figures 1C and 2B). The patient was discharged on Day 28, after altogether 10 days of prednisolone and ribavirin treatment. The reverse transcriptase–polymerase chain reaction of her nasopharyngeal aspirate was negative for SARS-CoV on Day 21. Her prednisolone dosage was reduced to 20 mg daily on discharge. She has attended our SARS outpatient clinic for altogether 15 weeks and remained completely well. She has been off all medications, including her gradually reducing course of oral prednisolone, for 7 weeks.
DISCUSSION With the help of characteristic findings on chest radiographs and high-resolution computed tomography, a significant rise in anti–SARS-CoV IgG and a positive reverse transcriptase– polymerase chain reaction showing the presence of SARS-CoV in the nasopharygneal aspirate of this patient (5), the diagnosis of SARS-CoV infection was confirmed on Day 14. However, the patient’s clinical features were different from those previously reported (1–3, 6). The patient did not have definite contact history with any patient who had SARS, although she frequently visited Amoy Gardens, a densely populated housing estate with a recent major community outbreak of SARS. Although previous
Figure 1. Chest radiographs of our patient (A ) on admission showing normal lungs, (B ) on Day 14 showing bilateral lower-zone ground-glass opacification and consolidation, and (C ) resolution of lung opacities on Day 28.
Case Report
Figure 2. High-resolution computed tomography (A ) on Day 14 showing consolidation in the right lower lobe and (B ) on Day 28 showing resolution of the consolidation Day 28.
reports showed most patients with SARS had definite contact history with patients with SARS (1–3, 7), this epidemiologic link could be hard to define when pockets of community infections existed. The experience in Hong Kong showed that some patients had acquired SARS even after a very brief visit to Amoy Gardens during the outbreak there. Although she fulfilled the diagnostic criteria of SARS, our patient is “atypical” in her indolent clinical course, which was
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also milder than that of other patients with SARS we had encountered (6). Whereas the persistent fever and chills not responding to antibiotic therapy was typical of SARS, her fever was unusual in that it subsided on Day 11, while her chest radiograph continued to deteriorate thereafter. For the vast majority of patients with SARS-CoV pneumonia, fever characteristically resolves completely, and usually overnight only after commencement of corticosteroids and ribavirin (1, 6, 7). Unusually, there was no history of other respiratory symptoms other than mild cough, and physical examination of the chest did not reveal any crackles or dullness. The pneumonic illness, liver dysfunction, and lymphopenia in SARS are known to respond to steroid therapy, thus suggesting that SARS-CoV infection could alter and upregulate the immune system (1, 7). The rapid improvement in clinical, radiologic, liver function and lymphopenia after steroid therapy in this lady, despite her indolent presentation, was characteristic of SARS-CoV infection (1, 6). The indolent nature and milder severity of her illness could possibly be the result of her taking azathioprine for mild graft-versus-host disease, which could also had been helped by the high-dose steroid regimen in her anti-SARS therapy. It follows that azathioprine or even other immunosuppressants might have a therapeutic role in SARS-CoV infection not responding to high-dose steroids, although the clinical efficacy of steroid and ribavirin remain unproven. Patients with SARS usually have abnormal chest radiographs on presentation (8). The mostly frequently seen shadows are predominantly lower zone ground-glass opacities, focal consolidation, or patchy consolidation (1). The air-space opacities may increase in size and extent with diffuse involvement of the lungs resulting in ARDS. However, our patient was noted to have increased lung infiltration over both lower zones only on Day 10, although this might have become apparent on high-resolution computed tomography earlier. The resolution of fever on Day 11 suggests that the disease was partly self-limiting in this patient. This is important, as there is no information or clinical experience on the clinical course of SARS-CoV infection among immunocompromised patients. The frequent need for hospitalization and attendance of medical facilities by these patients also put them at risk of exposure to SARS-CoV. Their familiarity and friendship with health care workers and fellow patients could theoretically make them very effective spreaders of SARS-CoV infection, should they suffer from indolent presentation as in our patient, whose prompt isolation had probably prevented cross infections in our institute. The recognition of SARS is not an easy clinical task, and the diagnosis of indolent presentation of SARS-CoV infection requires extreme vigilance in identification of potentially exposed patients with history of fever, and presence of respiratory symptoms, lymphopenia, and abnormal liver transaminases for isolation and subsequent confirmation by serial radiography, SARS-CoV identification measures, and clinical reevaluation (6). Experience from our case suggests that indolent presentation of SARS-CoV infection could occur in immunocompromised patients, although this needs to be confirmed by further studies. It is beyond the scope of this article to describe the details of infection control measures needed to control nosocomial transmission of SARS-CoV infection, although health care workers need to be particularly aware of this type of indolent presentation of SARS-CoV infection and be prepared to exercise strict isolation policy on encounters with such patients. Our institute continues to admit all patients suffering from fever with evidence of radiographic consolidation to isolation wards for further evaluation and exclusion of SARS-CoV infection, and this practice is anticipated to continue in our locality until a validated diagnostic test becomes available to permit early diagnosis of SARS-CoV infection sensitively and specifically.
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Pulmonary complications are common after bone marrow transplantation and account for significant morbidity and mortality (9). The risk factors for the pulmonary complications include immunodeficiency secondary to of the underlying disease and its treatment, conditioning regime, and development of graftversus-host disease (9). The commonly seen pulmonary illnesses developed in the later stage of bone marrow transplantation include opportunistic infections, chronic graft-versus-host disease, bronchiolitis obliterans, idiopathic pulmonary syndrome, radiation fibrosis, and bronchiolitis obliterans with organizing pneumonia. The latter closely resembles SARS in radiographic and high-resolution computed tomography appearances as they both tend to have lower-zone distribution and peripheral consolidation, although SARS-CoV pneumonia is not associated with lymphadenopathy or pleural effusion (1, 10). This radiologic resemblance is also interesting as SARS-CoV pneumonia and bronchiolitis obliterans with organizing pneumonia are probably largely immunologically mediated (10). Conflict of Interest Statement : M.F.L. has no declared conflict of interest; G.C.O. has no declared conflict of interest; B.L. has no declared conflict of interest; J.C.H. has no declared conflict of interest; W.H.S. has no declared conflict of interest; P.L.H. has no declared conflict of interest; P.C.W. has no declared conflict of interest; R.L. has no declared conflict of interest; W.K.L. has no declared conflict of interest; K.W.T. has no declared conflict of interest. Acknowledgment : The authors thank all health care workers at Queen Mary Hospital for their dedication and excellent care of our patients with SARS. They also thank Christina Yan and June Sun for their help in data collection, and Christine So for secretarial assistance.
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