Case Study: COVID-19 Management in Patients With Hematologic Malignancies

A 60-year-old man presented to the hospital with five days of fever, dry cough, and shortness of breath. Six years prior, he was diagnosed with κ light-chain multiple myeloma (MM), for which he received induction therapy with cyclophosphamide, bortezomib, and dexamethasone followed by high-dose melphalan and autologous hematopoietic cell transplantation. At the time of admission, he was on maintenance therapy with 10 mg lenalidomide on days 1 to 21 of 28 days, and dexamethasone with no evidence of disease. His vital signs showed a body temperature of 102.9°F, heart rate of 110 bpm, blood pressure at 131/74 mm Hg, respiratory rate of 41, and oxygen saturation of 94 percent at 4 L/min via nasal cannula.

The patient appeared diaphoretic and in acute respiratory distress, with rapid, shallow breathing. Diffuse inspiratory crackles were audible throughout the bilateral lung fields. Empiric broad-spectrum antibiotics were initiated, and the patient was admitted to the special pathogens unit. Within 12 hours after admission, the patient developed increased respiratory distress, and rapidly escalating oxygen requirements prompted his transfer to the intensive care unit (ICU). Upon arrival to the ICU, he was intubated for hypoxemic respiratory failure due to severe ARDS.

Lab results at presentation are shown in the Table. A chest X-ray on admission showed low lung volumes and bilateral atelectasis. Urinary antigens for Streptococcus pneumoniae and Legionella pneumophilia were negative. A polymerase chain reaction (PCR) –based respiratory viral panel was negative for influenza A/B, respiratory syncytial virus, adenovirus, human metapneumovirus, and parainfluenza 1-4. Nasopharyngeal reverse transcription-PCR for SARS-CoV-2 was positive, confirming the diagnosis of COVID-19 pneumonia. The patient was treated with hydroxychloroquine but showed no change in his clinical status. Given the patient’s elevated and rising serum interleukin (IL-6) level, C-reactive protein, and D-dimer, tocilizumab was administered with no appreciable clinical improvement. He was subsequently enrolled on a randomized clinical trial of remdesivir when it became available at our site. After two weeks of mechanical ventilation, the patient was successfully extubated and continues to clinically improve. 

Question 1: Is this patient’s presentation and clinical course typical of COVID-19 pneumonia?

Answer 1:

Yes. This case highlights several aspects of COVID-19 pneumonia that have been reported to date. Increasing age, immunosuppression, and medical comorbidities are poor prognostic factors for morbidity and mortality from SARS-CoV-2 infection.¹ This is particularly relevant for our patient with MM on lenalidomide and dexamethasone. It is not known precisely when our patient contracted the SARS-CoV-2 virus. However, a family member of the patient experienced a respiratory illness the week before the patient developed symptoms. This timeline is consistent with the reported median time of five days from initial SARS-CoV-2 infection to symptom onset.² Hallmark symptoms of SARS-CoV-2 infection include fever, sore throat, cough (typically nonproductive), shortness of breath, myalgias, and anosmia.^1-4 Importantly, the contribution of asymptomatic SARS-CoV-2 carriers to disease spread is increasingly recognized.³ Lymphopenia is a nearly universal finding in severely symptomatic patients. Additionally, markers of inflammation, including C-reactive protein, D-dimer, and IL-6, are often elevated in the setting of COVID-19 and may portend less favorable clinical outcomes. Mild elevation in liver transaminases has also been reported.⁴ At our institution, we have observed concomitant infections (viral, bacterial, and fungal) in some oncology patients with COVID-19; therefore, a complete infectious disease workup should be considered, especially in high-risk patients, even when COVID-19 is highly suspected or confirmed.

Unfortunately, our patient’s hypoxemic respiratory failure is also characteristic of severe COVID-19, with many patients experiencing rapid clinic deterioration and ultimately requiring invasive mechanical ventilation.⁴ To avoid aerosolization of viral particles, we avoid high-flow nasal cannula and noninvasive ventilation modalities. Preliminary experience suggests that early, controlled intubation decreases the risk of virus aerosolization and may improve clinical outcomes, although this is controversial. The most common radiographic findings are bilateral reticular nodular infiltrates and ground glass opacities^2,4; however, a proportion of patients may have normal plain film chest radiograph findings at the time of presentation. Chest computed tomography frequently demonstrates diffuse interstitial infiltrates in patients with known infection even if chest x-ray is unremarkable. Prolonged mechanical ventilation is necessary for many patients to recover and associated with a high in-hospital mortality rate. Renal failure requiring renal replacement therapies is a common complication in patients critically ill with COVID-19. Additionally, cardiomyopathy and fatal cardiac arrhythmias have been observed in patients with COVID-19 and warrant close clinical monitoring.^4,5

Question: What testing modalities are clinically available for COVID-19 testing?

Answer:

Currently, SARS-CoV-2 infection is diagnosed by RT-PCR from nasopharyngeal swab or other respiratory secretions (e.g., tracheal aspirate). In terms of assay performance, the specificity of PCR testing is quite high (99%), with a moderate sensitivity that varies across platforms (80-95%). Consequently, at our institution we recommend two separate tests at least 12 hours apart to confidently rule out SARS-CoV infection in symptomatic hospitalized patients. With improvements in test availability and multiplex capacity, test turnaround time continues to decrease but often depends on where the sample is analyzed (e.g., state reference, commercial, or hospital-based labs). Newer point-of-care testing may soon provide results within minutes; however, the sensitivity has been consistently lower than for laboratory-based techniques. Serologic testing for IgG and IgM antibodies against SARS-CoV-2 have recently been approved by the U.S. Food and Drug Administration (FDA), though few tests have been validated, and there is no evidence of association of antibody levels with clinically relevant immunity. This testing modality can determine if a person has been exposed to the virus and will be helpful for contact tracing, assessing asymptomatic carriers, and measuring efficacy of future SARS-CoV-2 vaccines. Much remains unknown about testing. If there is enough clinical suspicion for COVID-19 infection despite negative PCR assays, our practice is to send serologies and manage patients as if they have infection.

Question: Can you tell us about the investigational COVID-19 therapies this patient received?

Answer:

Yes. Hydroxycholoroquine has been used for decades to treat malaria and rheumatologic disorders. In a small study from China, hydroxychloroquine was reported to improve the time to symptom resolution in patients with COVID-19. As a result, the FDA has granted Emergency Use Authorization for hydroxycholorquine for patients with COVID-19. However, more recent data demonstrating a lack of clinical benefit of the combination of hydroxycholorquine and azithromycin, combined with prolonged QTc, underscore the need for additional prospective safety and efficacy data.⁷ A recent trial of lopinavir-ritonavir in patients with severe COVID-19 did not show a significant clinical benefit.⁸ Remdesivir, an adenosine analogue that inhibits viral RNA polymerase, has shown promising in vitro antiviral activity.^9,10 Based on these data, multiple clinical trials of remdesivir alone or in combination with other agents are ongoing.¹¹ Lastly, IL-6, among other cytokines, are often elevated in severe COVID-19 infection and monoclonal antibodies that block IL-6 signaling (i.e., tociluzumab, siltuximab, sarilumab) may be effective in mitigating the overly exuberant inflammatory response in patients with severe COVID-19. While our patient did not respond to tocilizumab, several patients at our institution have experienced marked improvements with IL-6 blockade. Several clinical trials of agents that block IL-6 are ongoing or near completion.¹¹

References:

1. Coronavirus (COVID-19). Centers for Disease Control and Prevention. 2020.
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4. Arentz M, Yim E, Klaff L, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington statev. JAMA. 2020;doi: 10.1001/jama.2020.4326. [Epub ahead of print].
5. Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;doi: 10.1001/jamacardio.2020.1017. [Epub ahead of print].
6. van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med. 2020;382:1564-1567.
7. Molina JM, Delaugerre C, Le Goff J, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect. 2020;doi: 10.1016/j.medmal.2020.03.006. [Epub ahead of print].
8. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N Engl J Med. 2020;doi: 10.1056/NEJMoa2001282. [Epub ahead of print].
9. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitrov. Cell Res. 2020;30:269-271.
10. Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov. 2020;19:149-150.
11. ClinicalTrials.gov.