Clinical characteristics of COVID-19 and active tuberculosis co-infection in an Italian reference hospital
- Claudia Stochino1,
- Simone Villa2⇑,
- Patrizia Zucchi3,
- Pierpaolo Parravicini3,
- Andrea Gori2,4 and
- Mario Carlo Raviglione2
- 1Phthisiology Unit, Sondalo Hospital, ASST Valtellina e Alto Lario, Sondrio, Italy
- 2Centre for Multidisciplinary Research in Health Science, University of Milan, Milan, Italy
- 3Department of Internal Medicine, ASST Valtellina e Alto Lario, Sondrio, Italy
- 4Infectious Diseases Unit, Department of Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Simone Villa, MD, Centre for Multidisciplinary Research in Health Science, University of Milan, Via Francesco Sforza 35, 20122, Milan, Italy. E-mail: simone.villa{at}unimi.it
Abstract
The COVID-19 infection rate was high in patient with active tuberculosis. Major clinical complications were seen only in two patients thus requiring ex novo oxygen supply, one of whom with advanced tuberculosis died. Nasal swab viral clearance was rapid.
The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), emerged in Wuhan, China, in December 2019. In February 2020, an outbreak was detected in Lombardy region, Italy, resulting in the first major outbreak outside Asia [1].
Tuberculosis (TB), the leading cause of death worldwide from a single infectious agent (1.5 million people per year) [2], like COVID-19, is mainly transmitted through the respiratory route and affects the lungs.
Risk factors such as advanced age and some co-morbidities, such as diabetes and chronic respiratory diseases, are associated with poor outcomes in both TB and COVID-19 [3]. However, only limited information about COVID-19 and active TB co-infection has been reported so far [4–6]. Concerns remain that COVID-19 could have a negative impact on the clinical course of TB and its ultimate outcome [7, 8].
This study describes clinical, radiological, and laboratory characteristics of a series of COVID-19 patients with concurrent active TB in a hospital in Sondrio province, Region Lombardy in northern Italy.
Patients with active TB admitted to the hospital were analysed to assess the impact of COVID-19 on their clinical course as well as radiologic and laboratory consequences of the co-infection. TB diagnosis relied mainly on Xpert MTB/RIF and chest radiography (CXR) followed by culture confirmation and phenotypic and genotypic drug susceptibility testing (DST). At the time of TB diagnosis, patients were also tested for human immunodeficiency virus (HIV). COVID-19 diagnosis was based on the results of the real-time, reverse transcriptase-polymerase chain reaction (rRT-PCR) for SARS-CoV-2 from nasopharyngeal swabs. Radiological results at COVID-19 diagnosis were compared with the most recent radiographs available prior to the onset of COVID-19 to assess any change in pulmonary TB (PTB)-related lesions. A patient was considered COVID-19 laboratory-negative if two consecutive swabs, ≥24 h apart, were negative. Follow-up swabs were performed after 14 days from diagnosis and then every 7 days [9]. Clinical data were recorded during a follow-up period of 6–41 days following the first positive swab. The study was approved by the Ethic Committee of Monza e Brianza (Code 3377). Categorical variables are reported as absolute frequencies and percentages, while continuous variables are reported using median and interquartile range (IRQ).
Among the 24 in-patients diagnosed with active TB, we identified 20 cases with COVID-19 co-infection. Of those, 14 patients were referred from other hospitals in northern Italy and were admitted between 3rd and 28th March 2020. On March 25, a patient (P01), hospitalised in a single room since March 14, underwent nasopharyngeal swab after reporting a documented COVID-19 case in the household. Since then, five patients (P02–06) with fever were tested and were positive. Subsequently, all the remaining patients were tested (P07–24): P07–17 were diagnosed with COVID-19 on March 31 and P18-20 who tested negatively on March 31 became positive on April 13. Four patients (P21–24) screened for SARS-CoV-2 had negative nasal swab results repeatedly and were excluded from analysis. Among the 20 TB patients diagnosed with COVID-19 co-infection, 12 (60%) were males and the median (IQR) age was 39 (27–47) years: considering country of birth, the median age were 37 (27–46) and 48 (47–60) years for foreign-born (85%) and Italian nationals, respectively. Overall, 50% of patients had a BMI<18.5 Kg·m−2 at admission and eight had co-morbidities but none had HIV co-infection (table 1). Three patients reported having been vaccinated with Bacillus Calmette-Guérin (BCG).
Nineteen patients (95%) had PTB and, among them, three (P11,P13-14) had also extrapulmonary involvement: two patients (P11 and P13) had renal and neurological (P11 with TB meningeal abscess and small brain granulomas; P13 with TB meningitis and encephalitis) localisation; whereas one (P14) patient had a disseminated form with pericardial, pleural, splenic, and bone TB. TB was diagnosed using Xpert MTB/RIF (18/19;95%); in 14 patients, the diagnosis was confirmed by culture. In one case diagnosis was confirmed by bone biopsy (1/19;5%). At admission, CXR showed a multilateral involvement in 12/19 (63%) cases. Only one patient (P19) had an exclusively extrapulmonary TB (abdominal lymph nodes) that was diagnosed through needle aspiration.
Five patients (P07,P10,P17–18,P20) were infected with a drug-resistant strain: three were isoniazid resistant (through genotypic DST in P10) and two were multidrug-resistant. The standard anti-TB treatment regimen (isoniazid, rifampicin, ethambutol, and pyrazinamide) was used in 14 cases, while in six patients therapy was tailored based on clinical characteristics and DST results. Hydroxychloroquine (200 mg twice a day) was administered to all patients with COVID-19 co-infection and was well tolerated. No antiviral therapy was administered since no patient met the condition of intensive case admission for its use. Patients requiring second-line anti-TB drugs (pretomanid, linezolid, terizidone, and clofazimine) for treatment of multidrug-resistant forms (P18 and P20) were monitored through electrocardiogram and no QT interval prolongation was observed.
The median time from TB diagnosis and SARS-CoV-2 detection was 30 (range 19–69) days. The comparison of CXR after COVID-19 diagnosis with the latest available one (on average 32 [range 7–88] days earlier) showed that in 12 patients (63%) TB lesions were reduced (on average 30 [range 7–88] days before), whereas seven patients (35%) had worsening TB lesions (on average 32 [range 14–57] days earliest) and in one with EPTB there was no change. At CXR, three patients (15%) (P02, P06, P20) had mild-to-moderate interstitial thickening associated with COVID-19, and one (P13) had ground glass pattern compatible with COVID-19 on computed tomography (CT) scan.
A general lymphocytopenia (total lymphocyte count <1500·mm−3) was detected in 13 patients (65%) and one patient (P18) had thrombocytopenia (platelet count <150×103·mm−3). Increased serum levels of transaminase (both aspartate aminotransaminase and alanine aminotransaminase) was observed in two cases (P19 and P20) who were known to have previously suffered from anti-TB drug-induced hepatitis. Nineteen (95%) patients high D-dimer levels (>250 ng·mL−1)–but only five (P01, P04, P06–07, P11) more than 2000 ng·mL−1 –and 11 of them (58%) had an increased ferritin concentration (>300 ng·mL−1). One patient, P19, affected by sickle cell anaemia, had a level of 5036 ng·mL−1 attributed to frequent blood transfusions.
Oxygen supplementation was required in four patients at admission (P02, P05, P08, P17); in three patients (P02,P08,P17) it was soon discontinued and in one reduced from 2 to 1 L·min−1 (P05). During hospitalisation, three patients required ex novo oxygen supply (P06, P11, P13) due haemoglobin desaturation below 95%. Among them, two had respiratory complications: one had a pneumothorax due to subpleural blebs rupture (P11) which required temporary oxygen supplementation until thoracic drainage, and one elderly patient (P06), with advanced PTB and cachexia, developed COVID-19 pneumonia and severe hypoxia (requiring 10 L·min−1 oxygen supplementation) dying 6 days after COVID-19 diagnosis.
Follow-up swabs were performed in 19 co-infected patients. In twelve patients (63%) the test converted to negativity after 14 days from the first nasal swab (P01,P03,P05,P07–10,P14–15,P18–20). Four additional patients (21%) had a negative test after 28 days (P4,P11–12,P16). In the three remaining patients, nasal swabs became negative on day 34 (P13) and day 41 (P02 and P17).
This is the first series of patients co-infected with TB and COVID-19 in one single care centre. In our series, 20 in-patients with TB (19 PTB) were diagnosed with COVID-19 through an active screening programme in the 24 in-patients in the ward implemented after the first six cases were identified (P01–06). In the immediate 3–4 weeks following COVID-19 diagnosis, the clinical course of TB and COVID-19 co-infection was generally benign and only one patient died (5% case fatality rate).
Several hypotheses can be made on the dynamics of the spread of the infection in the ward. First, prior to COVID-19 diagnosis in P01, subjects with TB could sit in common areas within the ward wearing a surgical mask. This policy probably facilitated transmission including through contamination of objects and surfaces. Second, transmission could have been caused by an infected staff wearing FFP-3 masks with exhalation valve that may have contributed to spreading viral particles when the wearer exhales [11]. Finally, it is possible that transmission occurred through occasional visitors who were allowed in the ward, although in limited numbers, until March 29 wearing surgical masks. In any case, this outbreak is the result of insufficient infection control practices compounded by a higher vulnerability of TB patients.
The impact of COVID-19 co-infection on the clinical course of active TB seems to be modest in this series. Apart from fever present in most patients, no major clinical deterioration was observed with the notable exception of the one who died. In most cases, TB lesions at CXR did not worsen and only four patients had signs of newly developed pneumonia. No patient was admitted to intensive care unit or mechanically ventilated. Severe respiratory insufficiency was only seen in the patient who died.
Biochemical tests did not show major deviations from the expected values, except for D-dimer levels and lymphocytopenia; more advanced testing of immune biomarkers is in progress. Clearance of the virus from nasal swabs was rapid in 63% of patients at day 14 from COVID-19 diagnosis. Finally, there was no drug-drug interactions between anti-TB drugs and hydroxychloroquine.
Our study requires some final comments. First, the low rate of clinical and radiological deterioration in our series may be associated to the young age of most patients, low frequency of other co-morbidities including HIV infection, low prevalence of MDR-TB, and the quality of healthcare services. Second, clinical symptoms may have been partly under-estimated due to cultural and linguistic barriers as the vast majority of patients were recent immigrants. Third, lung lesions caused by COVID-19 might have been over-looked due to the use of portable CXR at patient's bed instead of CT scan given the decision to prevent further nosocomial [10]. Finally, the duration of follow-up was limited to a few weeks thus not allowing assessment of longer-term outcomes which will be, however, assessed later.
In conclusion, the impact of COVID-19 on active TB appears to be clinically manageable with proper care. Rigorous infection control practices and personal protection devices are fundamental to prevent the risk of in-hospital transmission especially when dealing with a highly vulnerable population.
Footnotes
Author Contributions: Study concept and design: Gori A, Raviglione MC.
Acquisition of data: Stochino C, Zucchi P.
Analysis, or interpretation of data: Villa S.
Drafting of the manuscript: Villa S.
Critical revision of the manuscript for important intellectual content: Stochino C, Zucchi P, Parravicini P, Gori A, Raviglione MC.
Statistical analysis: Villa S.
Administrative, technical, or material support: Villa S, Zucchi P, Parravicini P.
Study supervision: Parravicini P, Gori A, Raviglione MC.
Support statement: None.
Conflict of interest: Dr. Stochino has nothing to disclose.
Conflict of interest: Dr. Villa has nothing to disclose.
Conflict of interest: Dr. Zucchi has nothing to disclose.
Conflict of interest: Dr. Parravicini has nothing to disclose.
Conflict of interest: Dr. Gori has nothing to disclose.
Conflict of interest: Dr. Raviglione has nothing to disclose.
- Received May 10, 2020.
- Accepted May 25, 2020.
- Copyright ©ERS 2020
This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.