We analyzed 13 confirmed cases of SARS-CoV-2 pneumonia patients with disease exacerbation after admission. Exacerbation of SARS-CoV-2 pneumonia does not always but indeed happen (13/120, 10.8%) among inpatients.
Review the age distribution of 13 patients, 11(11/13 85%) had exceeded 60 years old. The majority of patients (9/13 69%) had underlying comorbidities, including but limited to hypertension, diabetes, heart disease, chronic kidney disease, hepatic disease. Two patients under 60 years of age had obesity, hyperlipidemia (case1), and coronary artery disease, hypertension (case2) separately. Aging and underlying diseases may collaborate and contribute to the decline of host immunity that is the prerequisite of virus infection and disease exacerbation.
In this study, 10/13(76.9%) cases were female. This ratio seems to be quite contradictory to previous report on COVID-19 that claimed approximately 70% infections occur in male8. and also inconsistent with the proportion of male patients (67%) in severe SARS-CoV-2 pneumonia reported in another study8. Since this study had excluded patients admitted but has not been discharged or died before February 25, the total number and proportion of male patients could be underestimated.
Disease exacerbation mostly occurred in the second week of disease course (10/13, 76.9%). Patients (case 1,4,5,10,11,12,13) admitted early (within 7days) of the disease course had a relatively better prognosis than those (case 2,3,6,7,8,9) admitted later (after the first 7days). The early group demonstrated lower probability of complications and death. These results indicate that early admission is crucial to restrain deterioration and reduce mortality.
The overall mortality rate was 38.4%(5/13), and in critically severe cases,the mortality rate was 71.4%(5/7), slightly higher than former study8. These results may be attributed to the fact that the inclusion criteria of this study are different from those of the above studies. These data do not apply to the entire herd of infected patients.
In our study, fever and cough were the most common symptoms at hospital admission. Initial reports of the COVID-19 virus suggested that symptoms of SAR-CoV-2 pneumonia are similar to that of SARS and MERS, since most patients presenting with fever, cough, fatigue and hypodynamia9,10. However, one patient (case12) did not manifest fever during the entire course of disease. This is an 80 years old female patient presented to clinic with a complain of chest distress and palpitation. Since she was in the epidemic area, she underwent a CT scan which demonstrated pneumonia. Then nucleic acid test was administrated and this case is confirmed. Besides, patients presented diarrhea as the initial symptom of disease have been reported11. These extra-pulmonary initial symptoms deserve more attention outside of fever clinic.
Elevation of C-reaction protein, D-Dimer and lactate dehydrogenase, reduction of lymphocyte count and albumin are observed in more than half of the cases. Anemia, transaminase abnormality, elevated myocardial index and renal dysfunction are also detected as disease exacerbate. These changes are consistent with previous reports3,12,13.
Ground-glass opacity and consolidation are the main changes in CT imaging. CT manifestations are indicative of the exacerbation of pneumonia. In the process of exacerbation, more lobes were involved, range of GGOs were expanded and density of consolidation was increased. Additional signs on CT imaging include vascular enlargement, interlobular septal thickening in crazy-paving pattern, air bronchogram sign and discrete pulmonary nodules, which were previously reported in some studies14,15. CT imaging may serve as a standard method in the rapid diagnosis of COVID-19. Previous studies have reported that the sensitivity of chest CT is significantly greater than that of RT-PCR (98% vs 71%, respectively, p < .001) 16. And false negative rate is very low (3.9%)16. Nevertheless, CT is still incapable of distinguish between different viruses.
Nucleic acid RT-PCR testing is a standard test for suspected cases to confirm the SARS-CoV-2 infection. Sampling site plays an important role in virus detection. Case 10 was sampled at 4 sites (pharyngeal swab, urine, venous blood, stool) on the same day, only stool sample demonstrated positive result. The patient’s medical records showed severe diarrhea and significant weight loss, which suggests that stool specimen in patients presenting gastrointestinal symptoms is probably more sensitive to the virus than pharyngeal swabs. Controversial NAT results were also observed in case 8 whose sputum and urine sample were taken on the same day. Urine sampling is not of high priority in clinical routine due to lack of sufficient data to support it as a usual shedding route of coronavirus. For different sampling sites, bronchoalveolar lavage fluid exhibited the highest positive rate, followed by sputum, nasal and pharyngeal swabs showing poor positive rate in patients with fever17. Another study reported the detection rates of SARS-CoV-2 from sputum specimens are significantly higher than throat swabs18. SARS-CoV-2 has the ability to transmit through multiple routes19,20 and manifest diverse clinical symptoms which should be taken into account while sampling. We infer that while determine where specimens are collected, considering the location of initial symptoms may increase positive rate.
In 4 cases (case 6, 8, 9, 13), NAT showed ORF1ab negative and NP positive result. Low viral load might lead to this result since PCR kits currently used in clinical practice are generally more sensitive to the amplification of the N protein gene than ORF1ab. On the other hand, crossovers of other coronaviruses may cause the same result since ORF1ab sequence is more conservative than N protein gene. Patients presented single-positive result should be re-checked by test kits from a different manufacture or different test method.
NAT results has turned out to be controversial in 2 cases(case2,4). After discharge from hospital (20 days for case 2, 14 days for case 4), their NAT result reversed to be positive. It is not clear that whether these patients are still contagious. Virus isolation and antibody test may provide further confirmation. The shedding mode of virus might be relevant to a re-positive result of NAT. Intermittent shedding have been found in Epstein-Barr-virus infected patients21 and pulsed shedding of viruses in wildlifes22 have been reported. This may also suggest that SARS-CoV-2 has acquired the ability of chronic infection, as HIV integrates itself into the host's genome by reverse transcription23,24 and Hepatitis B virus invades into liver cells and transforms into covalently closed circular DNA25. But this hypothesis is yet unfounded and requires further investigation.
All medical treatment administrated in our cases suits clinical demands. The efficacy of antibiotics, antivirals, glucocorticoids is not discussed here since sample size is too small to summarize any conclusion.
This study has obvious limitations. First, only 13 cases were eventually involved. However, all included cases have intact medical records available to trace back and changes in severity grading over time is recorded in details. Second, due to the diversity of clinical needs, NAT sample site choosing changes in every case and CT examinations not administrated in 2 cases. Third, the course of illness is defined as the time interval between onset and outcome event in this study. Disregarding the incubation period leads to an underestimation of the actual span of disease course. Last but not least, as a retrospective study, recall bias and selection bias inevitably affected our assessment. Further studies on aggravating factors of pneumonia, early identification and prevention methods of exacerbation are needed.