COVID-19 isolation

Prof. Sharon Einav    |     25.05.2023

Patient summary

40-year-old female with immune suppression. Developed respiratory failure due to Sars-CoV2 (i.e. COVID-19 ARDS). 

Was placed on ECMO while in isolation. The patient is intubated. 

 

At this time she is in isolation for 14 days and PCR  is still positive (24 cycles).

Research Inquiries

  1. What are the guidelines for isolating immunosuppressed intubated patients with severe COVID-19 who are hospitalized? Is there any literature supporting these guidelines?

Conclusion

For the purpose of this research we examined guidelines for isolating immunosuppressed patients with severe COVID-19 who are hospitalized and intubated, along with supporting literature. 

 

Typically, individuals with moderate to severe immunocompromise require a minimum isolation duration of 20 days after symptom onset or the first positive viral test. Prolonged viral shedding can occur in these patients, regardless of disease severity. Experts differ in their approach to discontinuing isolation, with some favoring a test-based strategy and others using a symptom-based strategy if the patient is without fever and shows clinical improvement. 

 

According to the CDC guidelines (most recent update from August 2022), moderate to severely immunocompromised patients should isolate for a minimum of 20 days. Discontinuation of isolation requires two consecutive negative respiratory specimens obtained at least 24 hours apart using an antigen or nucleic acid amplification test. 

 

Some articles included in this research reported cases of extended viral shedding beyond the recommended 20-day isolation period in immunocompromised patients with varying degrees of immunosuppression. 

A systematic review ( published in Clinical Infection in Practice (Q3) in 2022 the SR includes 32 out of 2450 research articles published between January 2020 and January 2022) highlighted the limited significance of repeated testing of SARS-CoV-2 viral RNA in recovering patients to determine infectivity. It emphasized the necessity of a multi-tier approach for discontinuing isolation, taking into account patient host factors, symptoms, and severity. The study suggested that a combination of molecular and serological testing is more effective in guiding clinical decisions and formulating infection control policies, rather than relying solely on molecular testing.

 

The 2022 European Centre for Disease Prevention and Control (ECDC) guidelines support discontinuing isolation 20 days after symptom onset. However, a letter circulated by the Ministry of Health of Israel stipulates that patients requiring aerosol-generating medical procedures (AGPs) should be isolated and placed in an isolation room. However, the recommended duration for such isolation is not explicitly specified.

 

Limited data exist on person-to-person transmission from late shedding in immunocompromised patients despite multiple studies demonstrating their prolonged shedding of SARS-CoV-2. One case report documented transmission of the virus between hospitalized immunocompromised patients, occurring over 28 days after the index patient’s initial symptoms.

Medical Meta Findings​

For individuals with moderate to severe immunocompromise, the recommended isolation duration is typically extended to a minimum of 20 days after symptom onset (or the first positive viral test for asymptomatic cases). This is because such patients can exhibit prolonged shedding of viable viruses, irrespective of the severity of their disease.[1] [3]

The approach to discontinuing isolation varies among experts. Some prefer a test-based strategy, while others utilize a symptom-based strategy, provided the patient is afebrile and shows clinical improvement.

Test-based strategies 

Test-based strategies are useful for determining the duration of isolation in moderately/severely immunocompromised patients, as they consider the variable timeframe required for viral control. The CDC in the United States favors this approach.[1]

According to the CDC guidelines, updated in August  2022, Moderate to severely immunocompromised patients necessitate a minimum isolation duration of 20 days. The cessation of isolation should be determined through serial testing and consultation with an infectious disease specialist. The criteria for discontinuing isolation comprise two consecutive negative respiratory specimens obtained at least 24 hours apart using an antigen or nucleic acid amplification test. Furthermore, symptomatic patients must exhibit a fever resolution for at least 24 hours without antipyretic medication, improvement in other symptoms, and persistent loss of taste and smell should not prolong isolation. Re-testing for SARS-CoV-2 infection is recommended if symptoms worsen or relapse following isolation. If nucleic acid amplification tests remain persistently positive beyond 30 days, additional testing modalities like genomic sequencing or viral culture, under the guidance of an infectious disease specialist, may be warranted.

 

Extended viral shedding has been observed in immunocompromised patients with moderate to severe immunosuppression – Patients who have undergone hematopoietic stem-cell transplantation or received cellular therapies may shed viable SARS-CoV-2 for at least 2 months. A study published in The New England Journal of Medicine in December 2020 reported viable virus isolation from immunocompromised patients even after 20 days of symptom onset.[3] These patients had undergone stem-cell transplants or CAR T-cell therapy within the past 6 months. Despite shedding the virus for an extended period, these patients did not develop antibodies against the viral nucleoprotein and experienced severe cases of Covid-19.

In another case study published in December 2020, an immunocompromised patient with CLL and acquired hypogammaglobulinemia shed infectious SARS-CoV-2 for 70 days and had detectable viral RNA for 105 days after diagnosis.[4]

A January 2021 case study documented sustained viral replication for 119 days in a patient with refractory mantle cell lymphoma and B-cell immunodeficiency. The patient experienced multiple COVID-19 admissions over a 4-month period, indicating ongoing viral activity.[5]

Furthermore, an April 2022 case study highlighted the potential consequences of B-cell-depleting therapies on viral shedding and disease progression. It described a 335-day infection in an immunocompromised patient, showing unique mutations in the virus, including a deletion in the spike protein’s amino-terminal domain and the complete deletion of certain genes.[6] The patient intermittently tested positive for SARS-CoV-2 but exhibited mild or absent symptoms, suggesting the shedding of nonviable virus particles.

A recent prospective study, published in the Journal of Infectious Diseases (Q1, IF 7.759) in April 2023, provides valuable insights into the viral shedding patterns among immunocompromised patients with hematologic malignancies or transplant recipients[10]. The study involved a total of 41 patients.

According to the findings, the authors report that the immunocompromised patients demonstrated viable virus shedding for a median duration of 4 weeks.  

The authors emphasize the importance of exercising caution when deciding to de-isolate immunocompromised patients.

  • In a case study published in the International Journal of Infectious Diseases (Q1, IF 12.7) in June 2021, a case is presented where a hospitalized COVID-19 immunocompromised patient transmitted the virus to another immunocompromised patient more than 28 days after experiencing initial symptoms. [11] The researchers conducted whole genome sequencing of the viruses to confirm the transmission.

The authors highlight that severely immunocompromised patients, whose ability to clear the virus is compromised, may remain infectious for prolonged durations.



These studies emphasize the importance of considering prolonged viral shedding and potential viral evolution in immunocompromised individuals infected with SARS-CoV-2.

 

Nontest-based strategies 

Some experts endorse a nontest-based approach for patients who are clinically improved, particularly those with moderate immunocompromise. In this setting, isolation can be discontinued 20 days after symptom onset as in ECDC Guidelines on ending the isolation period for people with COVID-19 (2022).

The guidelines also note that for prolonged RT-PCR positivity (RNA shedding), high Ct values (≥30) indicate a low likelihood of transmissibility, whereas low Ct values (<24) suggest a higher probability of transmissibility. However, it is important to note that these thresholds are not standardized and vary among laboratories. When considering discontinuation of isolation, it is essential to assess the clinical and immune status of the case, along with the time since symptom onset and potentially more specialized genotyping.[7]

  • According to a systematic review published in Clinical Infection in Practice (Q3) in 2022 and cited by the National Institutes of Health (NIH) in the COVID-19 Treatment Guidelines[8], the data on the dynamics of SARS-CoV-2 infectivity indicates that 95% of samples become nonviable after 15 days in the general population, with a median duration of 11 days. However, in critical patients and immunocompromised individuals, viable viral shedding can persist for up to 2 and 3-4 months, respectively, with a median duration of 20 days.[9] This prolonged viral shedding, as observed in the study, contradicts the most recent guidance from the CDC regarding the shortened isolation duration. Hence, it is important to exercise caution when revising such protocols. 

Moreover, the review suggests that repeated testing of SARS-CoV-2 viral RNA in recovering patients does not correlate with infectivity. It emphasizes the necessity of adopting a multi-tier approach to discontinuing isolation, which takes into account patient host factors, disease symptomatology, and severity. The review suggests that a combination of molecular and serological testing is more effective in guiding clinical decisions and formulating infection control policies, rather than relying solely on molecular testing.

Ministry of Health of Israel SARS-CoV-2 hospitalized patients policy

  1. In January 2022, the Ministry of Health of Israel issued and circulated a letter regarding the isolation policy for hospitalized patients with SARS-CoV-2. The letter states that patients requiring aerosol-generating medical procedures (AGPs) must be placed in an isolation room but provides no information on the required duration of isolation.
 

2.Another letter (draft to date) circulated by the Ministry of Health of Israel, dated May 15, 2023, maintains the same isolation policy for hospitalized patients with SARS-CoV-2 but similarly provides no guidance regarding the duration of isolation.

References​

  1. Center for International Blood and Marrow Transplant Research (CIBMTR); National Marrow Donor Program (NMDP); European Blood and Marrow Transplant Group (EBMT); American Society of Blood and Marrow Transplantation (ASBMT); Canadian Blood and Marrow Transplant Group (CBMTG); Infectious Disease Society of America (IDSA); Society for Healthcare Epidemiology of America (SHEA); Association of Medical Microbiology and Infectious Diseases Canada (AMMI); Centers for Disease Control and Prevention (CDC). Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective. Bone Marrow Transplant. 2009 Oct;44(8):453-558. PMID: 20095071.

  2. https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.htmlacyclovir prophylaxis for preventing varicella-zoster virus disease after hematopoietic cell transplantation: no evidence of rebound varicella-zoster virus disease after drug discontinuation. Blood. 2007 Oct 15;110(8):3071-7. doi: 10.1182/blood-2007-03-077644. Epub 2007 May 21. PMID: 17515400.

  3. Aydillo T, Gonzalez-Reiche AS, Aslam S, van de Guchte A, Khan Z, Obla A, Dutta J, van Bakel H, Aberg J, García-Sastre A, Shah G, Hohl T, Papanicolaou G, Perales MA, Sepkowitz K, Babady NE, Kamboj M. Shedding of Viable SARS-CoV-2 after Immunosuppressive Therapy for Cancer. N Engl J Med. 2020 Dec 24;383(26):2586-2588. doi: 10.1056/NEJMc2031670. Epub 2020 Dec 1. PMID: 33259154; PMCID: PMC7722690.

  4. Avanzato VA, Matson MJ, Seifert SN, Pryce R, Williamson BN, Anzick SL, Barbian K, Judson SD, Fischer ER, Martens C, Bowden TA, de Wit E, Riedo FX, Munster VJ. Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with Cancer. Cell. 2020 Dec 23;183(7):1901-1912.e9. doi: 10.1016/j.cell.2020.10.049. Epub 2020 Nov 4. PMID: 33248470; PMCID: PMC7640888.

  5. Baang JH, Smith C, Mirabelli C, Valesano AL, Manthei DM, Bachman MA, Wobus CE, Adams M, Washer L, Martin ET, Lauring AS. Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 Replication in an Immunocompromised Patient. J Infect Dis. 2021 Jan 4;223(1):23-27. doi: 10.1093/infdis/jiaa666. PMID: 33089317; PMCID: PMC7797758.

  6. Nussenblatt V, Roder AE, Das S, de Wit E, Youn JH, Banakis S, Mushegian A, Mederos C, Wang W, Chung M, Pérez-Pérez L, Palmore T, Brudno JN, Kochenderfer JN, Ghedin E. Yearlong COVID-19 Infection Reveals Within-Host Evolution of SARS-CoV-2 in a Patient With B-Cell Depletion. J Infect Dis. 2022 Apr 1;225(7):1118-1123. doi: 10.1093/infdis/jiab622. PMID: 34940844; PMCID: PMC8755281.

  7. https://www.ecdc.europa.eu/en/publications-data/covid-19-guidance-discharge-and-ending-isolation

  8. https://www.covid19treatmentguidelines.nih.gov/special-populations/immunocompromised/

  9. Qutub M, Aldabbagh Y, Mehdawi F, Alraddadi A, Alhomsy M, Alnahdi A, Fakeeh M, Maghrabi A, Alwagdani M, Bahabri N. Duration of viable SARS-CoV-2 shedding from respiratory tract in different human hosts and its impact on isolation discontinuation polices revision; a narrative review. Clin Infect Pract. 2022 Jan;13:100140. doi: 10.1016/j.clinpr.2022.100140. Epub 2022 Feb 16. PMID: 35190799; PMCID: PMC8848577.

  10. Kang SW, Kim JW, Kim JY, Lim SY, Jang CY, Chang E, Yang JS, Kim KC, Jang HC, Kim D, Shin Y, Lee JY, Kim SH. Characteristics and risk factors of prolonged viable virus shedding in immunocompromised patients with COVID-19: a prospective cohort study. J Infect. 2023 Apr;86(4):412-414. doi: 10.1016/j.jinf.2023.01.024. Epub 2023 Jan 20. PMID: 36682630; PMCID: PMC9852259.

  11. Kaila V, Sirkeoja S, Blomqvist S, Rannikko J, Viskari H, Lyly-Yrjänäinen T, Syrjänen J. SARS-CoV-2 late shedding may be infectious between immunocompromised hosts. Infect Dis (Lond). 2021 Nov;53(11):880-882. doi: 10.1080/23744235.2021.1939891. Epub 2021 Jun 17. PMID: 34137349; PMCID: PMC8220436.

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