Fatal relapse of COVID-19 after recovery? A case report of an older Italian patient
Authors: Francesco Bellanti, Aurelio Lo Buglio, Giacomo Custodero, Lucia Barbera, Graziano Minafra, Marcella Montrano, Fabio De Biase, Gianluigi Vendemiale
Journal: Journal of Infection (2020)

Dear Editor, Even though knowledge on SARS-CoV-2 and COVID-19 improved significantly during the last months, several aspects remain a matter of debate. One of these aspects is related to the recommendation to confirm clearance of SARS-CoV-2, defining recovery and discharge from isolation. The European Centre for Disease Prevention and Control updated the guidance on discharge of people with COVID-19, considering different types of patients.1European Centre for Disease Prevention and Control. Guidance for discharge and ending of isolation of people with COVID-19. https://www.ecdc.europa.eu/en/publications-data/guidance-discharge-and-ending-isolation-people-covid-19. 2020.Google Scholar Common criteria for recovery include (1) resolution of fever ≥ 3 days or clinical improvement, and (2) two consecutive negative SARS-CoV-2 real-time Reverse Transcription Polymerase Chain Reaction (RT-PCR) in a 24-hour interval. Particularly, two consecutive negative SARS-CoV-2 RT-PCR test results are recommended for immunocompromised or severely ill patients, to exclude false negative results, especially in case of transfer to other units within the hospital or discharge to long-term care facilities. We report a fatal COVID-19 relapse in a very old lady transferred from a COVID-19 area to a COVID-19-free unit. On 19 October 2020, a 91-year-old woman presented with respiratory failure to the Emergency Room of our Hospital (Fig. 1A). Her medical history included type 2 diabetes, arterial hypertension, atrial fibrillation, chronic kidney disease, and mixed anxiety-depressive disorder. Chest-X-ray displayed a thickening of the interstitial plot in the right perihilar region (Fig. 1B1). The RT-PCR on the nasopharyngeal swab revealed the presence of SARS-CoV-2. Laboratory results showed a multiple organ dysfunction syndrome (Table 1). The patient was hospitalized in a COVID-19 department and treated with dexamethasone, piperacillin/tazobactam, daptomycin, enoxaparin, furosemide, amiodaron, bisoprolol, basal-bolus insulin therapy, and O2 by Venturi mask to keep a saturation above 94%.Table 1Laboratory results.VariableReference rangeAdmissionDay 5Day 9Day 13Day 16Day 20C-reactive protein (mg/L)0.0–5.0236.6*66*20.3*3.192.5*187.6*HS-Troponin I (ng/L)< 10.81250.2*269.0*161.9*197.5*D-dimer (ng/mL)< 500698*469385303Sodium (mmol/L)136–146126^137139137136144Potassium (mmol/L)3.5–5.35.03.94.04.64.25.0Chloride (mmol/L)97–11090^10298110106116*Oxygen (mmHg)> 8049^165898269^39^Carbon dioxide (mmHg)35 - 4528^29^27^24^27^29^Bicarbonates (mmol/L)22–2626.1*26.8*27.6*20.9^21.7^14.3^Blood urea nitrogen (mg/dL)10–50100*154*109*73*54*Creatinine (mg/dL)0.20–1.102.94*2.06*2.16*1.70*1.60*Glucose (mg/dL)70–110585*292*155*143*Calcium (mg/dL)8.8–10.69.68.4^Total protein (g/dL)6.1–8.36.84.9^Albumin (g/dL)3.2–5.02.8^2.76^Globulin (g/dL)0.50.42Aspartate aminotransferase (U/L)2–401145*222921Alanine aminotransferase (U/L)2–40821*245*78*36Total bilirubin /mg/dL)0.2–1.20.840.34Gamma glutamyl-transpeptidase (U/L)7–382827Alkaline phosphatase (U/L)30–1209657Procalcitonin< 0.514.8*2.71*0.420.111.00*1.88*White-cell count (per mm3)4000–10,00021,410*10,920*13,170*15,540*8070Hemoglobin (g/dL)12–1611.8^11.5^10.5^10.4^10.0^Hematocrit (%)36–4836.035.2^32.6^33.2^30.4^Platelet count (1000 per mm3)130–450215324308174112^Absolute neutrophil count (per mm3)1.6–6.518.67*9.17*10.73*14.35*7.18*Absolute lymphocyte count (per mm3)0.8–4.51.460.951.550.780.62^NT-BNP (pg/mL)< 180034,700*5460**The value in the patient was above the normal range. ^The value in the patient was below the normal range. HS, High Sensitivity; NT-BNP, N-Terminal Brain Natriuretic Peptide. Open table in a new tab *The value in the patient was above the normal range. ^The value in the patient was below the normal range. HS, High Sensitivity; NT-BNP, N-Terminal Brain Natriuretic Peptide. The patient's conditions improved significantly during the following 10 days, and at the 11th–12th day two consecutive negative SARS-CoV-2 molecular tests from nasopharyngeal swabs were reported. The patient was then transferred to a COVID-19-free department; antibiotic therapy, dexamethasone and oxygen therapy were discontinued on Day 14. After two days, the patient presented with fever, dyspnea, tachypnea, stranguria; nevertheless, an oxygen saturation of 97% in ambient air was detected. Laboratory exams showed a urinary tract infection sustained by E. faecium. A chest-X-ray described pulmonary venous congestion and diffuse interstitial thickening (Fig. 1B2). A nasopharyngeal swab resulted positive for SARS-CoV-2. A consultation by an infectious disease specialist concluded that the clinical manifestations were caused by a bacterial infection, and a retest positive for SARS-CoV-2 could be interpreted as viral gene fragments without active replication in a recovered patient. Consequently, treatment with paracetamol, cefepime, clarithromycin, and caspofungin was started. During the following two days, the patient remained apyretic and eupnoic, and the oxygen saturation was 95–97% in ambient air. On Day 20, she appeared dyspneic, chest auscultation revealed diffuse rales, and the oxygen saturation in ambient air lowered to 70%. Therapy with furosemide and methylprednisolone was promptly started, and the patient was administered non-invasive ventilation. The day after, chest-X-ray revealed diffuse, confluent pulmonary opacities (Fig. 1B3). A Computed Tomography of the chest showed massive interstitial and alveolar involvement, with bilateral pleural effusion (Fig. 1C). Immunoglobulins for SARS-CoV-2 were negative. Another RT-PCR for SARS-CoV-2 on nasopharyngeal swab resulted positive. An additional specimen was used for SARS-CoV-2 isolation test, as previously reported.2Lenoci G. Galante D. Ceci E. Manzulli V. Moramarco A.M. Chiaromonte A. et al.Sars-CoV-2 isolation from a 10-day-old newborn in Italy: a case report.IDCases. 2020; 22PubMed Google Scholar The viral replication was confirmed by the specific biomolecular test for SARS-CoV-2, and an impressive cytopathic effect was observed. The patient died on Day 22. The risk of recurrence or re-activation of SARS-CoV-2 infection is a burning topic that needs to be promptly addressed to avoid early discharge and end of isolation in patients with potentially contagious disease. The first retrospective report described a 9% proportion of SARS-CoV-2 re-activation in discharged patients, occurring with mild or no symptoms from 4 to 17 days after negative SARS-CoV-2 tests.3Ye G. Pan Z. Pan Y. Deng Q. Chen L. Li J. et al.Clinical characteristics of severe acute respiratory syndrome coronavirus 2 reactivation.J Infect. 2020; 80: e14-e17Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar A further observation found a 14.5% proportion of COVID-19 patients tested positive after discharge, and mild symptoms in 32% of them.4Yuan J. Kou S. Liang Y. Zeng J. Pan Y. Liu L. et al.Polymerase chain reaction assays reverted to positive in 25 discharged patients with COVID-19.Clin Infect Dis. 2020; 71: 2230-2232Crossref PubMed Scopus (107) Google Scholar A review considered 62 investigations on newly positive SARS-CoV-2 molecular test in recovered patients, describing that recurrence involved adults rather than older subjects, presenting with no or mild symptoms.5Dao T.L. Hoang V.T. Gautret P. Recurrence of SARS-CoV-2 viral RNA in recovered COVID-19 patients: a narrative review.Eur J Clin Microbiol Infect Dis. 2020; Crossref Scopus (91) Google Scholar Asymptomatic or mild symptomatic course of COVID-19 recurrence could be related to the immune response.6Gao G. Zhu Z. Fan L. Ye S. Huang Z. Shi Q. et al.Absent immune response to SARS-CoV-2 in a 3-month recurrence of coronavirus disease 2019 (COVID-19) case.Infection. 2020; Crossref Scopus (21) Google Scholar Our report is related to a severe relapse of COVID-19, preceded by two negative RT-PCR tests and clinical improvement. We hypothesize that our patient could not develop an efficacious immune response during the first days of COVID-19. Reasons for SARS-CoV-2 positive tests in previously recovered COVID-19 patients include false results, intermittent viral sloughing, infection with a different strain, or contamination.7Gao Z. Xu Y. Guo Y. Xu D. Zhang L. Wang X. et al.A systematic review of re-detectable positive virus nucleic acid among COVID-19 patients in recovery phase.Infect Genet Evol. 2020; 85Google Scholar A high rate of false negative RT-PCR has been described even when two consecutive tests were performed, suggesting prolonged viral clearance rather than recurrence or re-infection.8Mancuso P. Venturelli F. Vicentini M. Perilli C. Larosa E. Bisaccia E. et al.Temporal profile and determinants of viral shedding and of viral clearance confirmation on nasopharyngeal swabs from SARS-CoV-2-positive subjects: a population-based prospective cohort study in Reggio Emilia, Italy.BMJ Open. 2020; 10e040380Crossref PubMed Scopus (29) Google Scholar To distinguish between relapse and re-infection, a genetic characterization of the SARS-CoV-2 strain could be performed. A limitation of this report is related to the absence of viral sequencing analysis; nevertheless, we hypothesize that the patient suffered of a persistent infection in which RT-PCR from two consecutive nasopharyngeal swabs resulted false negative, rather than a recurrence. Another reason for re-detectable SARS-CoV-2 RNA in RT-PCR from nasopharyngeal swab after two negative tests may be related to permanence in the lower respiratory tract, and further replication followed by transport to the pharynx through the mucociliary apparatus.9Vargas-Ferrer J. Zamora-Mostacero V. Re-detectable positive RT-PCR test results in recovered COVID-19 patients: the potential role of ACE2.Disaster Med Public Health Prep. 2020; : 1-2Crossref PubMed Scopus (6) Google Scholar An important issue is related to contagiousness of this patient after the negative tests. The sample from our patient provided cultivable SARS-CoV-2, sustaining the hypothesis that she could be contagious. To conclude, this report suggests that SARS-CoV-2 infection may persist in the respiratory tract and give rise to fatal disease following an apparent recovery. Despite the need of larger studies, we recommend further monitoring of patients with predisposing factors to slow viral clearance because of immune system alterations. Notwithstanding pressure on healthcare system, these patients require to be checked for longer periods before discharge or transfer to COVID-19-free areas, to prevent the spread of SARS-CoV-2. None declared. None declared.