Rapidly Fatal COVID-19-associated Acute Necrotizing Encephalopathy in a Previously Healthy 26-year-old Man

Robert A. Raschke MD and Cristian Jivcu MD

HonorHealth Scottsdale Osborn Medical Center

Scottsdale, AZ USA

Case Presentation

A 26-year-old man presented to our Emergency Department at 0200 on the day of admission with chief complaints of subjective fever, leg myalgias, and progressive dyspnea of one week duration. An oropharyngeal swab PCR had revealed SARS-CoV-2 RNA three days previously. He had not received a SARS CoV-2 vaccination, but had made an appointment to receive it just a few days prior to the onset of his symptoms.

The patient had no significant past medical history, was taking no medications except for ibuprofen and acetaminophen over the past week, and did not take recreational drugs. He specifically denied headache and had no prior history of seizure.

On admission, his HR was 150 bpm (sinus), RR 22, BP 105/46 mmHg, temp 40.2° C. and SpO₂ 92% on room air. He was ill-appearing, but alert and oriented, his neck was supple and lung auscultation revealed bilateral rhonchi, but physical examination was otherwise unremarkable.

A CBC showed WBC 17.3 10³/uL, hemoglobin 13.9 g/dl, and platelet count 168 K/uL. A complete metabolic profile was normal except for the following: Na 135 mmol/L, creatinine 1.7 mg/dL, AST 95 and ALT 134 IU/L. D-dimer was 1.08 ug/ml (normal range 0.00-0.50 ug/ml), and ferritin 783 ng/ml. A urine drug screen was negative. Chest radiography showed subtle bilateral pulmonary infiltrates. CT angiography of the chest was negative for pulmonary embolism but showed bilateral patchy infiltrates consistent with COVID19 pneumonia. One liter NS bolus and dexamethasone 10mg were given intravenously, acetaminophen administered orally, and the patient was admitted to telemetry.

Shortly thereafter, the patient experienced a brief generalized seizure associated with urinary incontinence. He was stuporous post-ictally, exhibiting only arm flexion to painful stimuli. A stroke alert was called and radiographic studies emergently obtained. CT of the brain was normal and CT angiography of the head and neck showed no large vessel occlusion or flow-limiting stenosis, and a CT perfusion study (Figure 1) showed patchy Tmax prolongation in the right cerebellum and bilateral parietal occipital lobes “which may reflect artifact or relative ischemia” with no matching core infarct.

Figure 1. CT perfusion study showing mild bilateral posterior distribution ischemia (Tmax > 6 secs) without matching core infarct (CBF<30%), interpreted by a neuroradiologist as possible artifact.

The patient was transferred to the ICU at 10:00, and experienced a 40-second generalized tonic-clonic seizure shortly thereafter. Lorazepam 2mg was administered intravenously. The HR was 104, RR 21, BP 105/61, temp 36.5 C. and SpO₂ 96% on 2L /min nasal canula oxygen. On neurological examination, the Glasgow Coma Scale was 3, right pupil was 3mm, left pupil 2mm - both reactive, the gaze was disconjugate and directed downward, there was no blink to visual threat, and glabellar ridge pressure did not elicit grimace, but minimal arm flexion. The gag reflex was positive. Peripheral reflexes were 2+ with down-going toes bilaterally. Levetiracetam 1000mg bolus was administered intravenously. Glucose was 147 mg/dL. An EEG obtained at 12:00 showed diffuse bilateral slowing without seizure activity. A presumptive diagnosis of post-ictal encephalopathy was made. The patient seemed to be protecting his airway and nasal canula oxygen was continued.

The patient’s condition was not noted to significantly change over the next 12 hours. There were no episodes of hypoxia, hypotension or hypoglycemia. Around 0100 on the second day of hospitalization, the patient exhibited extensor-posturing and appeared to be choking on his oral secretions. HR rose to 135, BP 155/99, RR 12 and temp 37.8 C. His SpO₂ fell into the mid 80% range. He no longer had a gag or cough reflex and he was emergently intubated without complication. MRI (Figure 2) and MRV of the brain were emergently obtained. 

Figure 2. A: T2-weighted image demonstrating bilateral thalamic and L occipital white matter hypoattenuation. B: DWI and GRE images showing bilateral thalamic infarctions with hemorrhage. C: Representative DWI images of cerebrum and cerebellum and pons showing widespread diffusion restriction.

The MRI showed extensive diffusion restriction involving bilateral thalami, cerebellar hemispheres, pons, and cerebral hemispheres with scattered hemorrhage most obvious/confluent in the bilateral thalami.

Normal flow voids were present in intracranial arteries and venous structures. Partial effacement of the lateral and third ventricles was noted, with early uncal herniation. The MRV showed no evidence of dural venous sinus thrombosis.

At 05:00 of the second hospital day, it was noted that the patient’s pupils were dilated and unreactive and his respiratory rate was 16 – equal to the respiratory rate set on the ventilator. BP fell to 85/45 and norepinephrine infusion was started to maintain MAP >65 mmHg. STAT CT brain (Figure 3) showed hemorrhagic infarcts of the bilateral thalami with surrounding edema, interval development of low attenuation of the bilateral cerebrum and cerebellum, and mass effect with total effacement of fourth ventricle, basal cisterns and cerebral sulci consistent with severe cerebral edema.

Figure 3. STAT CT brain from 05:30 on the second hospital day showing bilateral thalamic infarctions and diffuse cerebral edema with effacement of the sulci and loss of grey/white differentiation.

Two neurologists confirmed the clinical diagnosis of brain death, including an apnea test. A venous ammonia level ordered that morning was not drawn. An autopsy was requested by the physicians, but not able to be obtained.

Discussion

Acute necrotizing encephalopathy (ANE) is a rarely-reported clinical-radiographic syndrome lacking pathopneumonic laboratory test or histological findings (1-3). It is characterized by an acute febrile viral prodrome, most commonly due to influenza or HHV-6, followed by rapidly progressive altered mental status and seizures. The most specific finding of ANE is necrosis of the bilateral thalami, appearing on MRI as hypoattenuated lesions on T2 and FLAIR images with diffusion restriction on DWI, and often with hemorrhage demonstrated on GRE images (as shown in figure 2 above). Symmetric multifocal lesions are typically seen throughout various other locations in the brain including the cerebral periventricular white matter, cerebellum, brainstem and spinal cord. Mizuguchi (who first described ANE in 1995) proposed elevation of serum aminotransferase without hyperammonemia, and cerebrospinal albuminocytologic dissociation (elevated CSF protein without leukocytosis) as laboratory criteria supporting the diagnosis of ANE (1,2). These were only partially evaluated in our patient. The mortality of ANE is 30% and significant neurological sequelae are common in survivors (2).

The clinical, radiographic and laboratory findings in our case are all characteristic of ANE, but our work-up was abbreviated by the patient’s fulminant presentation. The differential diagnosis includes hyper-acute forms of acute disseminated encephalomyelitis (ADEM) or acute hemorrhagic leukoencephalitis that may also occur after a viral prodrome and may be associated with diffuse white matter lesions (4,5), although bilateral thalamic necrosis is not characteristic of either of these entities. Examination of cerebral spinal fluid (CSF) for pleocytosis, oligoclonal bands, and testing for the myelin oligodendrocyte glycoprotein IgG autoantibody and the aquaporin-4 IgG serum autoantibody would have been indicated to further evaluate for the initial presentation of a relapsing CNS demyelinating disease (5,6). CSF examination would also have been helpful in ruling out viral encephalitis affecting the thalami, such as that caused by West Nile Virus (WNV) (7). An acute metabolic encephalopathy with diffuse brain edema, such as that caused by severe hyperammonemia associated with late-onset ornithine transcarbamylase deficiency (8) was not ruled out. Arterial or venous thromboembolism associated with COVID-19 were effectively ruled out by CT angiogram, CT perfusion and MRI and MRV findings.    

We found five previous case reports of ANE as a complication of COVID-19, ranging 33-59 years of age (9-13). The onset of altered mental status occurred 3, 4, 7,10 and 21 days after onset of COVID-19 symptoms and rapidly progressed to coma. Two had generalized seizures, one myoclonus and another “rhythmic movements” of an upper extremity. All had bilateral hypoattenuation of the thalami on CT and MRI with variable involvement of temporal lobes, subinsular regions, cerebellum, brainstem and supratentorial grey and white matter. Two patients had EEGs that showed generalized slow waves. All underwent examination of CSF with negative PCR tests for various common encephalopathy viruses including herpes simplex virus 1&2 and WNV - four reported CSF protein and cell counts, three of which demonstrated albuminocytologic dissociation. Three patients received IVIG. Two patients died on days 5 and 8 after onset of neurological symptoms. Two recovered after prolonged ICU care and the outcome of the third patient was not reported. ANE may be less rare than these few case reports suggest. A retrospective study carried out at 11 hospitals in Europe describes radiographic findings of 64 COVID-19 patients with neurological symptoms (14). The most common finding was ischemic stroke, but 8 patients had MRI findings consistent with encephalitis and two had findings characteristic of ANE.

The pathogenesis of ANE is unknown. Ten cases of fatal ANE with brain biopsy are reported (1,15-19). These showed diffuse cerebral edema, and hemorrhagic necrosis invariably involving the thalami. An exudative small vessel vasculopathy with endothelial necrosis was found in 7/10 patients (This could perhaps explain the early CT perfusion findings interpreted as artifactual in our patient). Demyelination or inflammatory infiltration of the brain or leptomeninges was absent. There has been conjecture that these pathological findings might be due to disruption of the blood brain barrier caused by hypercytokinemia but there is scant supportive evidence (20). 

There is no proven treatment for ANE. Corticosteroids, IVIg and plasma exchange have been previously used (3,9-11,21). Clinical trials are unlikely given the rarity of the disorder.

It was unfortunate that this young man had not availed himself of SARS CoV-2 vaccination. We did not make a pre-mortem diagnosis of ANE between his first abnormal CT brain at 0100 and his death at 06:00. We would have performed an LP, measured serum ammonia and given a trial of corticosteroids and IVIg if we had had more time.

References

1. Mizuguchi M, Abe J, Mikkaichi K, Noma S, Yoshida K, Yamanaka T, Kamoshita S. Acute necrotising encephalopathy of childhood: a new syndrome presenting with multifocal, symmetric brain lesions. J Neurol Neurosurg Psychiatry. 1995 May;58(5):555-61. [CrossRef] [PubMed]
2. Mizuguchi M. Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan. Brain Dev. 1997 Mar;19(2):81-92. [CrossRef] [PubMed]
3. Wu X, Wu W, Pan W, Wu L, Liu K, Zhang HL. Acute necrotizing encephalopathy: an underrecognized clinicoradiologic disorder. Mediators Inflamm. 2015;2015:792578. [CrossRef] [PubMed]
4. Marchioni E, Ravaglia S, Montomoli C, et al. Postinfectious neurologic syndromes: a prospective cohort study. Neurology. 2013 Mar 5;80(10):882-9. [CrossRef] [PubMed]
5. Manzano GS, McEntire CRS, Martinez-Lage M, Mateen FJ, Hutto SK. Acute Disseminated Encephalomyelitis and Acute Hemorrhagic Leukoencephalitis Following COVID-19: Systematic Review and Meta-synthesis. Neurol Neuroimmunol Neuroinflamm. 2021 Aug 27;8(6):e1080. [CrossRef] [PubMed]
6. López-Chiriboga AS, Majed M, et al. Association of MOG-IgG Serostatus With Relapse After Acute Disseminated Encephalomyelitis and Proposed Diagnostic Criteria for MOG-IgG-Associated Disorders. JAMA Neurol. 2018 Nov 1;75(11):1355-1363. [CrossRef] [PubMed]
7. Guth JC, Futterer SA, Hijaz TA, Liotta EM, Rosenberg NF, Naidech AM, Maas MB. Pearls & oy-sters: bilateral thalamic involvement in West Nile virus encephalitis. Neurology. 2014 Jul 8;83(2):e16-7. [CrossRef] [PubMed]
8. Cavicchi C, Donati M, Parini R, et al. Sudden unexpected fatal encephalopathy in adults with OTC gene mutations-Clues for early diagnosis and timely treatment. Orphanet J Rare Dis. 2014 Jul 16;9:105. [CrossRef] [PubMed]
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11. Delamarre L, Galion C, Goudeau G, et al. COVID-19-associated acute necrotising encephalopathy successfully treated with steroids and polyvalent immunoglobulin with unusual IgG targeting the cerebral fibre network. J Neurol Neurosurg Psychiatry. 2020 Sep;91(9):1004-1006. [CrossRef] [PubMed]
12. Dixon L, Varley J, Gontsarova A, Mallon D, Tona F, Muir D, Luqmani A, Jenkins IH, Nicholas R, Jones B, Everitt A. COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia. Neurol Neuroimmunol Neuroinflamm. 2020 May 26;7(5):e789. [CrossRef] [PubMed]
13. Elkady A, Rabinstein AA. Acute necrotizing encephalopathy and myocarditis in a young patient with COVID-19. Neurol Neuroimmunol Neuroinflamm Sep 2020, 7 (5) e801. [CrossRef]
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15. Kirton A, Busche K, Ross C, Wirrell E. Acute necrotizing encephalopathy in caucasian children: two cases and review of the literature. J Child Neurol. 2005 Jun;20(6):527-32. [CrossRef] [PubMed]
16. Mastroyianni SD, Gionnis D, Voudris K, Skardoutsou A, Mizuguchi M. Acute necrotizing encephalopathy of childhood in non-Asian patients: report of three cases and literature review. J Child Neurol. 2006 Oct;21(10):872-9. [CrossRef] [PubMed]
17. Nakano I, Otsuki N, Hasegawa A. Acute Stage Neuropathology of a Case of Infantile Acute Encephalopathy with Thalamic Involvement: Widespread Symmetrical Fresh Necrosis of the Brain. Neuropathology 1993;13: 315-25. [CrossRef]
18. Yagishita A, Nakano I, Ushioda T, Otsuki N, Hasegawa A. Acute encephalopathy with bilateral thalamotegmental involvement in infants and children: imaging and pathology findings. AJNR Am J Neuroradiol. 1995 Mar;16(3):439-47. [PubMed]
19. San Millan B, Teijeira S, Penin C, Garcia JL, Navarro C. Acute necrotizing encephalopathy of childhood: report of a Spanish case. Pediatr Neurol. 2007 Dec;37(6):438-41. [CrossRef] [PubMed]
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21. Okumura A, Mizuguchi M, Kidokoro H, et al. Outcome of acute necrotizing encephalopathy in relation to treatment with corticosteroids and gammaglobulin. Brain Dev. 2009 Mar;31(3):221-7. [CrossRef] [PubMed]

Cite as: Raschke RA, Jivcu C. Rapidly Fatal COVID-19-associated Acute Necrotizing Encephalopathy in a Previously Healthy 26-year-old Man. Southwest J Pulm Crit Care. 2021;23(5):138-43. doi: https://doi.org/10.13175/swjpcc039-21 PDF

Utility of Endobronchial Valves in a Patient with Bronchopleural Fistula in the Setting of COVID-19 Infection: A Case Report and Brief Review

Nazanin Sheikhan, MD¹, Elizabeth J. Benge, MD¹, Amanpreet Kaur, MD¹, Jerome K Hruska, DO², Yi McWhorter DO³, Arnold Chung MD⁴

¹Department of Internal Medicine, HCA Healthcare; MountainView Hospital, Las Vegas, NV, USA

²Department of Pulmonology, HCA Healthcare; MountainView Hospital, Las Vegas, NV, USA

³Department of Anesthesiology Critical Care Medicine, HCA Healthcare; MountainView Hospital, Las Vegas, NV, USA

⁴MountainView Cardiovascular and Thoracic Surgery Associates, HCA Healthcare; MountainView Hospital, Las Vegas, NV, USA

Abstract

Patients with COVID-19 pneumonia frequently develop acute respiratory distress syndrome (ARDS), and in severe cases, require invasive mechanical ventilation. One complication that can develop in patients with ARDS who are mechanically ventilated is a bronchopleural fistula (BPF). Although rare, the frequency of BPF in patients with COVID-19 pneumonia is increasingly recognized. Here, we present a 48-year old man with BPF associated with COVID-19 pneumonia. Treatment with a commercial endobronchial valve (EBV) system resulted in reduced air leak allowing for tracheostomy placement. Our case adds to a growing body of evidence suggesting that the presence of COVID-19 pneumonia does not hinder the utility of EBV’s in the treatment of BPF’s.

Abbreviation List

• ARDS = acute respiratory distress syndrome
• BIPAP = Bilevel Positive Airway Pressure
• BPF = Bronchopleural Fistula
• COVID-19 = Coronavirus Disease-2019
• CT = Computed Tomography
• CTA = Computed Tomography Angiography
• EBV = Endobronchial Valve
• HFNC = High Flow Nasal Cannula
• ICU = Intensive Care Unit
• RML = Right Middle Lobe
• RUL = Right Upper Lobe
• SARS-CoV-2 = Severe Acute Respiratory Syndrome Coronavirus-2
• VATS = Video-Assisted Thoracoscopic Surgery

Introduction

The COVID-19 pandemic has resulted in over one hundred million infections worldwide, in addition to millions of deaths (1). A less common sequelae of COVID-19 is bronchopleural fistula (2). A bronchopleural fistula is an abnormal sinus tract that forms between the lobar, main stem, or segmental bronchus, and the pleural space (3). BPF is typically treated by surgical repair, via a video-assisted thoracoscopic surgical approach (VATS) (3). Bronchoscopic approach with placement of airway stents, coils or transcatheter occlusion devices can be considered for those who are not suitable for surgical intervention (3).  A newer therapeutic modality for bronchopleural fistulae are endobronchial valves, which have been used successfully to treat COVID-19 patients diagnosed concurrently with bronchopleural fistulae (4). 

Here, we present a case of a critically ill patient developing a bronchopleural fistula with a concurrent COVID-19 infection, whose respiratory status was stabilized with an endobronchial valve.  To our knowledge, this is one of four case reports of a bronchopleural fistula arising in the setting of COVID-19.

Brief Review of Endobronchial Valves in COVID-19

Several other studies report success using endobronchial valves to treat bronchopleural fistulae in patients with COVID-19 pneumonia. One case series documents two cases of COVID-19 pneumonia complicated by bacterial super-infections, in which both patients experienced pneumothorax and persistent air leaks after mechanical invasive ventilation.  Both patients were successfully treated via EBV positioning. These researchers speculate that the severe inflammation associated with COVID-19 related ARDS induces inflammatory-related tissue frailty, pre-disposing lung tissue to damage via barotrauma, and the subsequent development of BPF (5).  

Another case documents the treatment of a 49-year-old male with COVID-19 pneumonia who was treated with steroids and tocilizumab. He also had a 3-week history of persistent air leak, which was successfully treated with an EBV. This team emphasizes that the thick, copious sections evident in patients afflicted by COVID-19 pose a risk for EBV occlusion. They highlight the importance of medically optimizing the patient and draining the air leak to mitigate the potential of this procedural complication developing (4).

In conjunction with the treatment course presented in our case, these case reports provide compelling evidence indicating that endobronchial valves can be successfully used to treat persistent air leaks in patients with COVID-19 pneumonia.

Case Presentation

Our patient is a 48-year-old male with a medical history significant for essential hypertension and Type 1 diabetes mellitus who presented to the emergency department complaining of acute onset generalized weakness, shortness of breath, and a near-syncopal event that had occurred the day prior. Vital signs on admission showed an oxygen saturation of 86% on ambient air, respiratory rate of 18 breaths per min, heart rate of 111 beats per min with a temperature of 37.6°C. He was tested for SARS-CoV-2 on admission and was found to be positive.

Initial computed tomography (CT) chest showed diffuse bilateral ground-glass opacities compatible with COVID-19 pneumonia. On admission, his inflammatory markers were elevated, with C-reactive protein 4.48 mg/dL, ferritin 1230 ng/ml, lactate dehydrogenase 281 IU/L, and D-dimer 0.76 mg/L. He received 1 dose of tocilizumab, convalescent plasma, as well as 5-day course of Remdesivir. His oxygen requirement increased as well as his work of breathing requiring High Flow Nasal Cannula (HFNC) and subsequently Bilevel Positive Airway Pressure (BiPAP); patient was transferred to the medical intensive care unit (ICU) 17 days after admission requiring intubation. Computed tomography angiography (CTA) chest could not be obtained to rule out pulmonary embolism as patient was too unstable. Patient was started on Heparin drip empirically which had to be discontinued due to gastrointestinal bleeding. He had worsening oxygenation, ventilator asynchrony, with P:F ratio of 47, requiring high-dose sedation and neuromuscular blockade, as well as prone positioning. Repeat CT chest on day 21 demonstrated bilateral pneumothoraces and pneumomediastinum as well as interval worsening of diffuse ground glass infiltrates (Figure 1), requiring bilateral chest tube placement.

Figure 1. Computed tomography chest showing pneumomediastinum, bilateral pneumothoraces, and diffuse ground glass attenuation of the lungs bilaterally.

On the 34th day of admission, he developed a right-sided tension pneumothorax likely secondary to ongoing severe ARDS, requiring replacement of dislodged right chest tube. Patient subsequently had worsening of right pneumothorax requiring an additional second chest tube placement. Patient developed persistent air leak concerning for right bronchopleural fistula. On hospital day 42, patient underwent intrathoracic autologous blood patch with persistence of large air leak. After interdisciplinary conference with cardiothoracic surgery, pulmonary, and the ICU team, it was decided that patient is not a surgical candidate hence interventional pulmonology was consulted for EBV placement to facilitate chest tube removal and ventilator weaning.

Patient underwent fiberoptic bronchoscopy on hospital day 52; pulmonary balloon was used to sequentially block the right mainstem, bronchus intermedius, and basilar segments. The air leak was recognized to be coming from right middle lobe (RML) and the apex of the right upper lobe (RUL) status post placement of two endobronchial valves in the medial and lateral segments of the RML (Figure 2).

Figure 2. Bronchoscopic view of endobronchial valves.

The RUL could not be entered secondary to angulation and technical inability of the instruments to achieve a sharp bend. Post-bronchoscopy, patient had 50 mL reduction in air leak resulting in improvement of his ventilator settings such that a tracheostomy could be safely performed. Left-sided chest tube was removed with resolution of pneumothorax. Repeat CT chest on hospital day 115 demonstrated persistent right bronchopleural fistula (Figure 3).

Figure 3. Computed tomography chest showing bronchopleural fistula in the right middle lobe and collapsed and shrunken right middle lobe with endobronchial occlusion stents at the central airway. Yellow arrow showing endobronchial valves and red arrows showing bronchopleural fistula

The patient is currently pending transfer to a long-term acute care hospital for aggressive physical therapy and eventual transfer to a tertiary center for lung transplantation evaluation.

Discussion

Scientific research has moved at an unprecedented speed in an attempt to shed light on the manifestations of COVID-19. The most common presentation of COVID-19 includes cough, fever, shortness of breath, and new onset anosmia and ageusia (6).

Common complications include coagulopathy, pulmonary emboli, and in severe cases, acute respiratory distress syndrome (7). Bronchopleural fistulae have emerged as a rare but known complication of COVID-19. This pathology is traditionally seen as a post-surgical complication arising from lobectomy or pneumonectomy (8). All cause mortality secondary to bronchopleural fistulae are high; with mortality rates ranging from 18-67% (8).

A relatively novel therapeutic modality for bronchopleural fistulae are endobronchial valves, which have been used in patients who are not candidates for surgery, such as our patient (9). They work as a one-way valve that allow the pathologically trapped air to exit the respiratory system, but not enter (4).

Differential diagnoses for bronchopleural fistulae include alveolar pleural fistulas and empyema (11). Alveolar pleural fistulas are abnormal communications between the pulmonary parenchyma, distal to a segmental bronchus, and the pleural space, while bronchopleural fistulas are more proximal; representing abnormal connections between a mainstem, lobar, or segmental bronchus and the pleural space (12). These pathologies are differentiated with direct visualization on bronchoscopy, as was demonstrated in our patient (12).

There are currently no official statistics on the epidemiology of bronchopleural fistulae in COVID-19. A disappointing aspect of our case was the lack of complete resolution of the patient’s air leak after the placement of the endobronchial valve. While the patient’s condition did improve after the valve was placed, he continued to suffer from respiratory illness related to his bronchopleural fistula. Although complete remission was not achieved, the endobronchial valve placement did facilitate respiratory recovery sufficient enough to facilitate a tracheostomy. The patient was then stabilized for eventual transfer to a long-term acute care facility, where he will undergo physical therapy and await lung transplantation. It is important to emphasize that while the endobronchial valve was not curative, it stabilized the patient for possible future curative treatments.  

Conclusion

Despite their rarity, bronchopleural fistulas are a pulmonary complication of COVID-19. Although the insertion of the endobronchial valve in our patient resulted in a reduction of the air leak as opposed to complete resolution, this case still emphasizes a therapeutic benefit of endobronchial valves in such instances. Overall, our case demonstrates the importance of clinical vigilance in the face of unusual pulmonary complications related to COVID-19, and that treatment of these complications requires flexibility and creativity.

References

1. WHO Coronavirus (COVID-19) Dashboard [Internet]. World Health Organization. World Health Organization; [cited 2021May31]. Available from: https://covid19.who.int/ 
2. Hopkins C, Surda P, Kumar N. Presentation of new onset anosmia during the COVID-19 pandemic. Rhinology. 2020 Jun 1;58(3):295-298. [CrossRef] [PubMed]
3. Miesbach W, Makris M. COVID-19: Coagulopathy, Risk of Thrombosis, and the Rationale for Anticoagulation. Clin Appl Thromb Hemost. 2020 Jan-Dec;26:1076029620938149. [CrossRef] [PubMed]
4. Talon A, Arif MZ, Mohamed H, Khokar A, Saeed AI. Bronchopleural Fistula as a Complication in a COVID-19 Patient Managed With Endobronchial Valves. J Investig Med High Impact Case Rep. 2021 Jan-Dec;9:23247096211013215. [CrossRef] [PubMed]
5. Donatelli P, Trenatacosti F, Pellegrino MR, et al. Endobronchial valve positioning for alveolar-pleural fistula following ICU management complicating COVID-19 pneumonia. BMC Pulm Med. 2021 Sep 27;21(1):307. [CrossRef] [PubMed]
6. Salik I, Vashisht R, Abramowicz AE. Bronchopleural fistula. StatPearls [Internet]. 2020 Aug 27. [CrossRef]
7. Cardillo G, Carbone L, Carleo F, Galluccio G, Di Martino M, Giunti R, Lucantoni G, Battistoni P, Batzella S, Dello Iacono R, Petrella L, Dusmet M. The Rationale for Treatment of Postresectional Bronchopleural Fistula: Analysis of 52 Patients. Ann Thorac Surg. 2015 Jul;100(1):251-7. [CrossRef] [PubMed]
8. Sarkar P, Chandak T, Shah R, Talwar A. Diagnosis and management bronchopleural fistula. Indian J Chest Dis Allied Sci. 2010 Apr-Jun;52(2):97-104. [PubMed]
9. Pathak V, Waite J, Chalise SN. Use of endobronchial valve to treat COVID-19 adult respiratory distress syndrome-related alveolopleural fistula. Lung India. 2021 Mar;38(Supplement):S69-S71. [CrossRef] [PubMed]
10. Musani AI, Dutau H. Management of alveolar-pleural fistula: a complex medical and surgical problem. Chest. 2015 Mar;147(3):590-592. [CrossRef] [PubMed]
11. Mehta HJ, Malhotra P, Begnaud A, Penley AM, Jantz MA. Treatment of alveolar-pleural fistula with endobronchial application of synthetic hydrogel. Chest. 2015 Mar;147(3):695-699. [CrossRef]  [PubMed]

Acknowlegements

This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities. 

Cite as: Sheikhan N, Benge EJ, Kaur A, Hruska JK, McWhorter Y, Chung A. Utility of Endobronchial Valves in a Patient with Bronchopleural Fistula in the Setting of COVID-19 Infection: A Case Report and Brief Review. Southwest J Pulm Crit Care. 2021;23(4):109-14. doi: https://doi.org/10.13175/swjpcc046-21 PDF 

Arizona Hospitals and Health Systems’ Statewide Collaboration Producing a Triage Protocol During the COVID-19 Pandemic

Patricia A. Mayer, MD

David H. Beyda, MD

C. Bree Johnston, MD

Department of Bioethics and Medical Humanism and Medicine, The University of Arizona College of Medicine-Phoenix, Phoenix, AZ USA

Abstract

We describe the process by which all hospitals and health systems in Arizona, normally competitors, rapidly cooperated to develop a statewide protocol delineating how to allocate scarce resources during the COVID-19 pandemic should triage be required anywhere in the state. Eight physician ethicists from seven different health systems created the Addendum* (see editor's note after Abstract), which was accepted by all hospitals and health systems, approved by the State Disaster Medical Advisory Committee (SDMAC), and then formally adopted by the Arizona Department of Health Services (ADHS). In addition, the entire state developed a plan to “stick together” such that no facility would be forced to triage unless all were overwhelmed. Because we are unaware of any other state’s hospitals and health systems producing and committing to a shared triage protocol and plan, we believe this experience can serve as a model for other locales during the absence of sufficient state or federal guidance.

Editor's Note

The Addendum initially posted on ADHS has been removed. It appears to have been altered including removal of the authors. To see the original Addendum click here.

Abbreviations

• ADHS: Arizona Department of Health Services
• CMO: Chief Medical Officer
• CSC: Arizona Crisisi Standards of Care Plan, 3rd edition 
• SDMAC: State Disaster Medical Advisory Committee

The Challenge

Potential shortages of ventilators and other scarce resources during COVID-19 compelled creation of plans to allocate resources fairly (1). Without protocols, resources would be allocated on a first come first serve basis, which is inefficient and ethically problematic (1-4). Without a cohesive state plan, public confusion combined with uneven resources could lead to “hospital shopping” with vastly different individual outcomes that would likely benefit patients with greater social or economic advantages and be determined by geography rather than medical criteria.  

The Goal  

Because the existing Arizona Crisis Standards of Care Plan, 3^rd edition (CSC, 2) was deemed too non-specific to apply usefully in the pandemic, representatives from hospitals and hospital systems across the state, including small rural hospitals, competing private hospital systems, and  federal agencies (Indian Health Service and the Veteran’s Administration) sought a common triage protocol to addend the CSC. The goal was to create  a protocol accepted by  all hospitals, health care systems and ADHS.

Background

The pandemic caused severe and previously unknown shortages of personal protective equipment and life-sustaining equipment and therapies (6).  Much has been written about the need to allocate scarce resources in a manner that is fair, consistent, and based on sound ethical principles. Multiple states, cities, and health systems have shared their processes and protocols for triage during the pandemic (7,8)  However, integration between disparate systems has proved challenging at both the local, state and federal levels. Arizona is the sixth largest state in the country and the fourteenth most populous, with five-sixths of the population concentrated in two main metropolitan areas:Phoenix and Tucson. In addition, Arizona is home to twenty-one Native American tribes/nations. Most of the state is rural, distances from populated areas to health care facilities can be great, and access to health care is unevenly distributed. In Arizona health insurance coverage of the population is 45.1% employer, 5.2% non-group, 21% AHCCCS (Arizona’s Medicaid equivalent), 21.6% Medicare, 1.5% Military, and 11.1% uninsured (9).

Triage ethics differ from “usual” clinical ethics in which the lens is the individual patient and all patients have access to life-sustaining treatments.  hen life-sustaining resources are insufficient (e.g., pandemics, war), the concentration of the lens shifts from the individual good to the greater community (10). This shift is not only challenging for health care workers but also for a society that is increasingly divided and distrustful of experts. Therefore, it was clear that any protocol had to be fair, transparent and uniform across the state in order to be  and acceptable. This necessitated cooperation between organizations traditional in competition with each other that lacked a solid framework for this kind of emergency cooperation.

Creation and Adoption

In the early months of 2020, New York City and Italy were epicenters of the pandemic, and the world watched as they were overwhelmed with cases causing a shortage of beds and personal protective equipment. In response, Arizona hospitals health systems rapidly   their existing triage protocols and the state CSC. Therefore, amid predictions for a major surge in Arizona by summer 2020, Phoenix area hospital chief medical officers (CMOs) created the Triage Collaborative.  The first meeting laid a foundation for seamless collaboration since all participants, CMOs or their physician designees, were empowered to make decisions during the meetings without delay . This framework, uniquely possible due to the acute time pressure of the pandemic, enabled broader, more streamlined collaboration than had previously been possible between organizations that were normally in competition.

At the second meeting a week later, with representatives from the entire state  ADHS proposed a “Surge Line”. This 24/7 state-run hotline accessible to all Arizona healthcare providers   rapid transfers of COVID-19 patients to needed levels of care possible due to its ability to monitor statewide resource availability. All agreed to take part in the Surge Line, and it was rapidly implemented (11) Notably, and critical to success of the Surge Line, participation  was mandated and insurers  required to cover transfers and COVID-19 treatment at in-network rates by the Governor’s Executive Order 2020-38 in late May (12).  

On April 9, the Governor issued Executive Order 2020-27 which called for immunity from civil liability “in the course of providing medical services in support of the State’s public health emergency for COVID-19… (including) triage decisions…based on…reliance of mandatory or voluntary state-approved protocols …” (13). This  the necessity of a state-approved protocol. ADHS agreed to consider any protocol presented to them by the medical community.  

Driven by that Order, the Collaborative immediately shifted from sharing individual protocols to developing the needed statewide protocol  In addition, the Collaborative committed to cooperation agreeing that no facility would have to triage unless the entire state was overwhelmed  (14). To create the protocol  writing group of eight  from seven different systems volunteered to begin work immediately.

The writing goup reviewed the existing CSC and individual system protocols for suitability and agreed a new protocol was required that would be transparent, ethically sound  and reflect current best practices. After reviewing protocols from other states and literature on triage ethics, the group agreed on  goal: maximize the number of lives saved while treating patients without discrimination.

ADHS convened the State Disaster Medical Advisory Committee (SDMAC) in mid-June where the Addendum was discussed and approved.  ADHS then accepted and published the final COVID-19 Addendum: Allocation of Scarce Resources for Acute Care Facilities (15). The SDMAC was reconvened again in late June and recommended activation of the CSC, including the Addendum. The formal activation of the CSC by the Governor and ADHS on June 29 was unprecedented and signaled the ability to proceed with triage per the Addendum if needed. Arizona experienced its first major surge shortly thereafter, in July 2020. (for Timeline see Table 1 below).

Ethical Considerations

After a great deal of discussion, the writing group agreed on several key concepts:

1. Goals of care should be assessed as the first step in triage so that patients who do not desire ventilators or ICU beds will not compete for scarce resources that are unwanted (10).
2. The best available acute assessment score (e.g., SOFA, PELOD) should be utilized as an initial triage tool but should not be used alone (6-8).
3. Limited life expectancy should be included as a triage factor.
4. The protocol should avoid categorical exclusions and instead be based on prioritization criteria.
5. Perceived quality of life should not be considered.
6. The value of all lives must be explicitly recognized with triage criteria never used to deny resources when they are not scarce.
7. Criteria is only to prioritize patients when resources are scarce.
8. Criteria must not include any ethically irrelevant discriminatory criteria including race, ethnicity, national origin, religion, sex, disability, age, or gender identity.
9. Patients should be re-assessed and re-prioritized periodically based on their clinical course and continued likelihood of benefit.
10. Where “ties” occur in priority scores, the group must agree on which other factors to consider.
11. An explicit statement rejecting reallocation of personal/home ventilators (or any other durable medical equipment) in order to further protect patients with chronic respiratory conditions or disabilities was essential.

The Process

Bringing together the various health systems was remarkably seamless . However, the group faced a tight timeline to complete the protocol to prepare for a potential emergency.

Although members of the writing group agreed on the primary goal (e.g., maximizing number of lives saved), reaching consensus on other principles (e.g., how to incorporate life expectancy, life cycle, and instrumental concerns) was more challenging. However, over a short but intense time, members were able to reach decisions that all “could live with”.

Previous articles have advocated considering not only the number of lives saved using an acute assessment tool but incorporating other considerations, such as maximizing the number of years of life saved and using life cycle considerations (19,20). While the writing group agreed, members expressed concern about possible unintended consequences with those criteria. First, groups that have faced institutional racism and lifelong health disparities were more likely to have a shorter life expectancy and could face “double jeopardy” in triage protocols, particularly if comorbidities more prevalent in communities of color were used (21-4). Likewise, older patients would often be disadvantaged with these criteria. Group members felt strongly that use of life-years saved should be tempered to address these concerns and so elected to include near term life expectancy and the Life Cycle principle. Other issues included whether and how to prioritize pediatric patients, pregnant women, and single caretakers (25,26).

The group did agree to prioritize healthcare and other frontline workers in case of equal scores, not because of greater estimation of “worth” but because of the instrumental value they serve in the community and as an acknowledgement of their increased risk.

While the writing group did resolve issues in a way all parties “could live with”, members recognized ongoing discussions and updates would be important. For instance, after our Addendum was created, a strong case was made that triage policies should also promote population health outcomes and mitigate health inequalities (23). We echo the need to grapple with how best to address these equity and justice concerns. And although no protocol can perfectly reconcile all tensions we hope the Addendum reflects our sincere attempt to balance competing considerations fairly, ethically, and in a way that could be widely implemented if needed.  

The Team 

Arizona demonstrated a collaboration between all its hospitals and health systems with a subgroup of physician-ethicist representatives writing, employees at ADHS formatting and supporting the work, the SDMAC endorsing it, and the ADHS then accepting and publishing the Addendum with the agreement of the Governor’s’ office.

The Follow-up 

Arizona survived both the July 2020 and the January 2021 surges without resorting to triage and all hospitals and health systems continue to cooperate. The state Surge Line continues to function and as of Feb 1 had transferred over 3700 patients across the state. We remain acutely aware of the ongoing challenges of public perception, news reports, and social media, particularly in a society as divided as the U.S. is today. Already, the Addendum has been mis-characterized on social media as allowing health care providers to refuse scarce resources to older people and those with disabilities. We particularly hope that further conversations occurring outside the acute impending emergency will allow time for public engagement, which will provide valuable input and may mitigate inaccurate perceptions of the criteria used. Meantime, we believe our statewide transparent approach, with the support of ADHS, provided a novel approach and contributed to the state avoiding triage during the worst of our surges.

Conclusion

We believe the cooperation of   in developing a shared triage Addendum  represents a unique contribution and may provide a model for other localities facing public health emergencies requiring rapid decisive action.

References

1. ADHS. COVID-19 Addendum: Allocation of Scarce Resources in Acute Care Facilities, Recommended for Approval by State Disaster Medical Advisory Committee (SDMAC) 6/12/2020.  Available at https://www.azdhs.gov/documents/preparedness/epidemiology-disease-control/infectious-disease-epidemiology/novel-coronavirus/sdmac/covid-19-addendum.pdf.
2. Ventilator allocation guidelines. Albany: New York State Task Force on Life and the Law, New York State Department of Health, November 2015 , available at https://www.health.ny.gov/regulations/task_force/reports_publications/#allocation
3. Ferraresi M. A coronavirus cautionary tale from Italy: don’t do what we did. Boston Globe. March 13, 2020.  Available at https://www.bostonglobe.com/2020/03/13/opinion/coronavirus-cautionary-tale-italy-dont-do-what-we-did/
4. Sprung CL, Danis M, Iapichino G, et al. Triage of intensive care patients: identifying agreement and controversy. Intensive Care Med. 2013 Nov;39(11):1916-24. [CrossRef] [PubMed]
5. ADHS. Arizona Crisis Standard of Care Plan, 3rd ED. 2020; Available at: https://www.azdhs.gov/documents/preparedness/emergency-preparedness/response-plans/azcsc-plan.pdf
6. Ranney ML, Griffeth V, Jha AK. Critical Supply Shortages - The Need for Ventilators and Personal Protective Equipment during the Covid-19 Pandemic. N Engl J Med. 2020 Apr 30;382(18):e41. [CrossRef] [PubMed]
7. Berger JT. Imagining the unthinkable, illuminating the present. J Clin Ethics. 2011 Spring;22(1):17-9. [PubMed]
8. White DB, Lo B. A Framework for Rationing Ventilators and Critical Care Beds During the COVID-19 Pandemic. JAMA. 2020 May 12;323(18):1773-1774. [CrossRef] [PubMed]
9. KFF Health Policy Analysis, State Health Facts, accessed March 15, 2020  at https://www.kff.org/other/state-indicator/total-population/?currentTimeframe=0&selectedRows=%7B%22states%22:%7B%22arizona%22:%7B%7D%7D%7D&sortModel=%7B%22colId%22:%22Location%22,%22sort%22:%22asc%22%7D
10. Berger JT. Imagining the unthinkable, illuminating the present. J Clin Ethics, 2011. 22(1): 17-9.
11. Villarroel L, Christ, CM, Smith L et al. Collaboration on the Arizona Surge Line:  How Covid-19 Became the Impetus for Public, Private, and Federal Hospitals to Function as One System. NEJM Catalyst, Jan 21, 2021, available at https://catalyst.nejm.org/doi/full/10.1056/CAT.20.0595
12. Office of Governor Doug Ducey. Executive Order: 2020-38: Ensuring Statewide Access to Care for COVID-19 Arizona Surge Line. AZ Governor. Published May 28, 2020.
13. Office of Governor Doug Ducey. Executive Order : 2020-27: The “Good Samaritan” Order Protecting Frontline Healthcare Workers Responding to the COVID-19 Outbreak”. AZ Governor. Published April 9, 2020.
14. Feldman SL, Mayer PA. Arizona Health Care Systems’ Coordinated Response to COVID-19-“In It Together”. JAMA Health Forum. Published online August 24, 2020. [CrossRef]
15. ADHS. COVID-19 Addendum: Allocation of Scarce Resources in Acute Care Facilities, Recommended for Approval by State Disaster Medical Advisory Committee (SDMAC) 6/12/2020.  Available at https://www.azdhs.gov/documents/preparedness/epidemiology-disease-control/infectious-disease-epidemiology/novel-coronavirus/sdmac/covid-19-addendum.pdf
16. Lambden S, Laterre PF, Levy MM, Francois B. The SOFA score-development, utility and challenges of accurate assessment in clinical trials. Crit Care. 2019 Nov 27;23(1):374. [CrossRef] [PubMed]
17. Leteurtre S, Duhamel A, Salleron J, Grandbastien B, Lacroix J, Leclerc F; Groupe Francophone de Réanimation et d’Urgences Pédiatriques (GFRUP). PELOD-2: an update of the PEdiatric logistic organ dysfunction score. Crit Care Med. 2013 Jul;41(7):1761-73. [CrossRef] [PubMed].
18. Straney L, Clements A, Parslow RC, Pearson G, Shann F, Alexander J, Slater A; ANZICS Paediatric Study Group and the Paediatric Intensive Care Audit Network. Paediatric index of mortality 3: an updated model for predicting mortality in pediatric intensive care*. Pediatr Crit Care Med. 2013 Sep;14(7):673-81. [CrossRef] [PubMed]
19. White DB, Lo B. A Framework for Rationing Ventilators and Critical Care Beds During the COVID-19 Pandemic. JAMA. 2020 May 12;323(18):1773-1774. [CrossRef] [PubMed]
20. Emanuel EJ, Persad G, Upshur R, Thome B, Parker M, Glickman A, Zhang C, Boyle C, Smith M, Phillips JP. Fair Allocation of Scarce Medical Resources in the Time of Covid-19. N Engl J Med. 2020 May 21;382(21):2049-2055. [CrossRef] [PubMed]
21. Cleveland Manchanda E, Couillard C, Sivashanker K. Inequity in Crisis Standards of Care. N Engl J Med. 2020 Jul 23;383(4):e16. [CrossRef] [PubMed]
22. Price-Haywood EG, Burton J, Fort D, Seoane L. Hospitalization and Mortality among Black Patients and White Patients with Covid-19. N Engl J Med. 2020 Jun 25;382(26):2534-2543. [CrossRef] [PubMed]
23. White DB, Lo B. Mitigating Inequities and Saving Lives with ICU Triage during the COVID-19 Pandemic. Am J Respir Crit Care Med. 2021 Feb 1;203(3):287-295. [CrossRef] [PubMed].
24. Yancy CW. COVID-19 and African Americans. JAMA, 2020. 323(19): 1891-1892. [CrossRef] [PubMed]
25. Antommaria AH, Powell T, Miller JE, Christian MD; Task Force for Pediatric Emergency Mass Critical Care. Ethical issues in pediatric emergency mass critical care. Pediatr Crit Care Med. 2011 Nov;12(6 Suppl):S163-8. [CrossRef] [PubMed]
26. Beyda DH. Limited Intensive Care Resources: Fair is What Fair Is Current Concepts in Pediatric Critical Care by the Society of Critical Care Medicine (2015 Edition): 55-59.
27. White DB, Lo B. Mitigating Inequities and Saving Lives with ICU Triage during the COVID-19 Pandemic. Am J Respir Crit Care Med, 2021. 203(3): 287-295.

Acknowledgments

The authors would like to acknowledge ADHS as well as all of their collaborators from the Arizona hospitals and health systems including Abrazo Healthcare and Carondelet Healthcare Phoenix, Tucson & Nogales; Banner Health System; Canyon Vista Medical Center; CommonSpirit Arizona Division Dignity Health; Havasu Regional Medical Center; Honor Health; Indian Health Service; Kingman Regional Medical Center; Northern Arizona HealthCare; Phoenix Children’s Hospital; Summit Healthcare; Tucson Regional Medical Center; University of Arizona College of Medicine; Veteran’s Administration; Valleywise Health; Yavapai Regional Medical Center; Yuma Regional Medical Center.

Cite as: Mayer PA, Beyda DH, Johnston CB. Arizona Hospitals and Health Systems’ Statewide Collaboration Producing a Triage Protocol During the COVID-19 Pandemic. Southwest J Pulm Crit Care. 2021;22(6):119-26. doi: https://doi.org/10.13175/swjpcc014-21 PDF

Choosing Among Unproven Therapies for the Treatment of Life-Threatening COVID-19 Infection: A Clinician’s Opinion from the Bedside

Robert A. Raschke, MD

HonorHealth Scottsdale Osborn Medical Center

Scottsdale, AZ USA

We are clearly in unprecedented times. As clinicians watch patients die from COVID-19 infection in the ICU, many feel they cannot wait for clinical trials to prove that various proposed therapies are efficacious. Treatments for which any rationale suggest the possibility of benefit are being administered to patients and the literature abounds with reports of case series or poorly-designed observational trials in which small numbers of patients seem to have favorable outcomes when given these unproven therapies (1). In many cases, these reports are made globally available via social networking without the benefit of peer-review or are being published despite severe methodological flaws that would not have been acceptable prior to the COVID-19 outbreak. 

Standard therapy for COVID-19 has recently been published by the Surviving Sepsis Campaign, which have taken a conservative, evidence-based approach (2). But many clinicians are not able to maintain such equipoise in the face of catastrophe. Therefore, I propose an approach to consideration of bedside implementation of unproven therapies for life-threatening COVID-19 for comment and criticism. None of the therapies discussed below have even marginally-acceptable empirical evidence of clinical benefit in patients with COVID-19, so let us put critical appraisal of the literature aside for the moment, and accept that we cannot evaluate these therapies using the normal rules of evidence-based practice (3), application of which would exclude all from further consideration were this any other disease than COVID-19.

I will focus on four unproven therapies that are currently being given to patients with COVID-19 infection: hydroxychloroquine (4), tissue plasminogen activator (tPA) and heparin for presumed pulmonary microthrombosis (5), immunosuppressive treatment of “cytokine storm” (6), and transfusion of convalescent serum (7).

I based my opinions on these four unproven therapies on the following principles:

1. COVID-19 is a viral pneumonia. Although it may prove to have some distinctive features, it is likely to be similar to other viral pneumonias (such as SARS CoV-1, MERS, and H1N1 influenza) in terms of its clinical manifestations and response to therapy. We are more likely to gain helpful insights by looking at previous clinical data related to viral pneumonia than to data regarding various noninfectious entities such as high-altitude pulmonary edema or pulmonary venous occlusive disease, as some authors have suggested. COVID-19 viral pneumonia is unlikely, a priori, to respond to therapies that have never shown clinical benefit in the treatment of other viruses, particularly viral pneumonias.
2. Demonstration of in-vitro activity rarely translates into clinical efficacy (8,9). In-vitro activity should be a basis for clinical trials, not bedside implementation.
3. If unproven therapies are to be given, their safety must be an important consideration. First do no harm.
4. We should be willing to apply any treatment recommendation we make for patients to ourselves or beloved family members.

Based on these principles, I propose the following:

Hydroxychloroquine. The non-specific anti-viral properties of chloroquine and hydroxychloroquine were demonstrated in cell cultures 40 years ago. Although active in vitro against Dengue, HIV, Ebola, Influenza and other viruses, this has never convincingly translated into clinical effectiveness (9). A large cohort study focusing on prevention of influenza pneumonia included over 4000 patients receiving HCQ, and showed that they had an increased risk of hospitalization for pneumonia compared to controls (10). Given this long track record, it seems unlikely that HCQ will suddenly be found to have clinical anti-viral benefit in 2020. When it is nevertheless given, care should be exercised to monitor QTc, especially if used in conjunction with other QTc-prolonging drugs like azithromycin and/or in patients with cardiomyopathy.

tPA and heparin. A high incidence of venous thromboembolism has been observed in some cohorts of COVID-19 patients, as has previously been described in patients with H1N1 pneumonia (11).  Standard thromboprophylaxis should be employed and venous thromboembolism should be diagnosed and treated in patients with COVID-19 infection. However, some clinicians are administering tPA and therapeutic-dose heparin to patients with COVID-19 and elevated D-dimer in the absence of documented DVT or PE, based on the theory that these patients have microvascular thrombosis requiring treatment. Several large multicenter RCTs examined the use of human activated protein C (Xigris®) to prevent/treat microvascular thrombosis in patients with severe sepsis and convincingly demonstrated no clinical benefit (12). There is no other infectious disease for which the use of tPA or treatment-dose heparin has been proven to be clinically beneficial in the absence of standard indications related to documented venous thromboembolism. Lytic/antithrombotic therapy has a relatively high potential for causing life-threatening hemorrhage. In my opinion, it should not be employed without support from well-designed clinical trials. 

Cytokine Storm or HLH. The terms cytokine storm and hemophagocytic lymphohistiocytosis (HLH) have been used to describe similar (perhaps identical) maladaptive immune responses to viral infections. HLH has been well-described in H1N1 pneumonia, SARS-CoV-1 and MERS. There is a rich history of (mostly) observational clinical research supporting the use of immunosuppressive therapies including steroids, anakinra and tocilizumab to treat HLH secondary to viral infection (13). Although immunosuppression can be associated with life-threatening secondary opportunistic infections, treating secondary HLH in selected patients is an approach with a long track record and could be considered standard therapy in Covid19 patients fulfilling HLH diagnostic criteria.

Convalescent Serum. The use of convalescent serum is supported by low-quality observational data going back over 100 years. Although never proven effective in well-designed clinical trials, prior reports in patients with Spanish influenza, SARS-CoV-1 and H1N1 all suggest potentially significant reductions in mortality with acceptable safety (14-16). This therapy is more difficult to operationalize, requiring (expedited) FDA approval, collection, processing and testing of neutralizing antibody titers by a licensed blood bank (17), however based on the principles outlined above, its benefit/harm ratio seems to support its use as an investigational therapy in patients with life-threatening COVID-19.

References

1. Booth CM, Tannock IF. Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence. Br J Cancer 2014;110:551-5. [CrossRef] [PubMed]
2. Alhazzani W, Møller MH, Arabi YM, et al. Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19). Crit Care Med. 2020 Mar 27. [Epub ahead of print]. [CrossRef] [PubMed]
3. Guyatt GH, Sackett DL, Cook DJ. Users' guides to the medical literature. II. How to use an article about therapy or prevention. A. Are the results of the study valid? Evidence-Based Medicine Working Group. JAMA. 1993 Dec 1;270(21):2598-601. [CrossRef] [PubMed]
4. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial [published online ahead of print, 2020 Mar 20]. Int J Antimicrob Agents. 2020;105949. [CrossRef] [PubMed]
5. Wang J., Hajizadeh N, Moore EE, et al. Tissue plasminogen activator (tpa) treatment for COVID‐19 associated acute respiratory distress syndrome (ARDS): a case series. J Thromb Haemost. 2020 (in press). [CrossRef] [PubMed]
6. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-4.[CrossRef] [PubMed]
7. Duan K, Liu B, Cesheng L, Zhang H, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020 Apr 6. pii: 202004168. [CrossRef] [PubMed]
8. Seyhan, A.A. Lost in translation: the valley of death across preclinical and clinical divide - identification of problems and overcoming obstacles. Transl Med Commun. 2019;4:18. [CrossRef]
9. Dyall J, Gross R, Kindrachuk J, et al. Middle east respiratory syndrome and severe acute respiratory syndrome: current therapeutic options and potential targets for novel therapies. Drugs. 2017;77:1935-66. [CrossRef] [PubMed]
10. Vanasse A, Courteau J, Chiu Y, Cantin A, Leduc R. Hydroxychloroquine: an observational cohort study in primary and secondary prevention of pneumonia in an at-risk population. MedRxIv .April 10, 2020. [CrossRef]
11. Bunce PE, High SM, Nadjafi M, Stanley K, Liles WC, Christian MD. Pandemic H1N1 influenza infection and vascular thrombosis.Clin Infect Dis. 2011 Jan 15;52(2):e14-7.
12. Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012 May 31;366(22):2055-64. [CrossRef] [PubMed]
13. Yildiz H, Van Den Neste E, Defour JP, Danse E, Yombi JC. Adult haemophagocytic lymphohistiocytosis: a review. QJM. 2020 Jan 14. [Epub ahead of print] [CrossRef] [PubMed]
14. Luke TC, Kilbane EM, Jackson JL, et al. Meta-analysis: convalescent blood products for spanish influenza pneumonia: a future H5N1 treatment?. Ann Intern Med. 2006;145:599-609. [CrossRef] [PubMed]
15. Hung IF, To KK, Lee CK, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011 Feb 15;52(4):447-56. [CrossRef] [PubMed]
16. Yeh KM, Chiueh TS, Siu LK, et al. Experience of using convalescent plasma for severe acute respiratory syndrome among healthcare workers in a Taiwan hospital. J Antimicrob Chemother. 2005 Nov;56(5):919-22. [CrossRef] [PubMed]
17. US Food & Drug Administration. Recommendations for Investigational COVID-19 Convalescent Plasma. April 8, 2020. Available at:https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma (accessed 4/10/20).

Cite as: Raschke RA. Choosing among unproven therapies for the treatment of life-threatening covid-19 infection: a clinician’s opinion from the beside. Southwest J Pulm Crit Care. 2020;20(4):131-4. doi: https://doi.org/10.13175/swjpcc026-20 PDF 

Further COVID-19 Infection Control and Management Recommendations for the ICU

Robert A. Raschke MD

HonorHealth Osborne Medical Center

Scottsdale, AZ USA

An ad hoc committee of intensivists from the Phoenix area has been meeting via Zoom. They are sharing some of their thoughts and recommendations. Like the previous ICU recommendations published in SWJPCC (1), these are not necessarily evidence-based but based on recent experience and published experience with previous coronavirus outbreaks such as SARS. They are meant to supplement CDC recommendations, not to conflict or restate them.

Infection control outside the rooms of suspected/confirmed COVID-19 patients.

1. All healthcare workers should be allowed to exercise droplet precautions at all times while at work.
2. All staff should wear a single surgical mask per day to see all non-COVID patients and for rounds. The mask mitigates droplet spread bidirectionally between patients and HCWs and also helps prevent inadvertent touching of the nose and mouth.
3. Treat all code patients with airborne / standard / contact precautions
4. Use MDIs in preference to SVNs (as long as MDIs hold out)
5. Reduce unnecessary staff and visitor traffic in all patient rooms. Avoid duplication of effort, repeated chest examinations with a stethoscope, in the same day by various doctors and nurses, are unlikely to benefit the care of most patients. Don’t enter the patient’s room without a specific purpose and try to perform multiple required tasks with each room entry.
6. Hand washing before/after: doorknobs, eating, using a computer, phones, googles.
7. Phones – use your own cellphone rather than shared landlines. Use speaker phone so you don’t have to touch your face.
8. Consolidate computer use temporally and geographically. Clean your entire workstation (keyboard, mouse, surrounding desktop) before and after each use.
9. Keep track of and clean any object on your person that might be contaminated with fomites. This includes any medical instruments that you touch will your gloved hands while seeing patients (stethoscope, pen light, googles, etc). Leave these at work.
10. When walking down hallways, don’t touch things.

Patients under investigation or with known COVID-19.

1. Avoid use of high-flow nasal cannula (HFNC) or BiPAP. This in opposition to surviving sepsis campaign recommendations, but data from SARS-CoV-1 show that non-invasive ventilation was associated with increased risk of infection of health care workers (2).
2. Use metered dose inhalers (MDIs) instead of small volume nebulizers (SVNs).
3. Use N95 or PAPR during aerosol-producing procedures such as obtaining nasopharyngeal swab for SARS-CoV-2 RT-PCR, HFNC, BiPAP, bronchoscopy, intubation, breaking ventilator circuit for any reason, extubation, tracheostomy.
4. Consider early intubation. Prepare the bag mask with a high-efficiency particulate air (HEPA) filter and attempt rapid sequence intubation with fiberoptic laryngoscope.
5. If available, powered air-purifying respirators (PAPR) using P100 HEPA filters (filter >99.97% of 0.3 um particles) should be considered over N-95 (filter 95% of 5 um particles) masks during this high risk procedure based on prior reports of SARS CoV-1 transmission to health care workers (HCW) wearing N95 masks PAPR protects the entire head and neck of the HCW, but requires additional training on donning/duffing.
6. If unable to wear PAPR, we recommend N95 masks, gowns and gloves, with googles instead of open face shielded masks. Aerosolized particles are more likely to pass around shields into eyes during these high-risk procedures. Also recommend hats and foot protection.
7. The smallest number of personnel required to safely perform the intubation should be present in the room. Fiberoptic laryngoscopy may be preferred over direct laryngoscopy to reduce exposure to aerosolized particles.
8. Once intubated:
   1. Be sure all connections in the ventilator circuit are tight and do not break the circuit casually.  
   2. Place HEPA filter on exhalational limb of ventilator.
   3. Obtain bronchial secretions using closed-circuit suction device

Code blue patients.

1. Use the same precautions as for COVID-19 patients in all patients for whom a code is called.
2. We recommend aerosol, contact and standard precautions and eye protection for all code team members for all codes - regardless of whether COVID-19 is suspected. There is no time in a code to determine the likelihood the patient has COVID-19, and bag-masking and intubation will aerosolize the patient’s respiratory secretions.
3. A HEPA filter should be placed between the patient and the bag mask to reduce aerosolization of viral particles into the atmosphere.

Diagnosis of COVID-19.

The sensitivity of RT-PCR for COVID-19 is currently uncertain, but preliminary data suggests it may only be in the range of 70% for nasopharyngeal swabs and respiratory secretions. Bronchoscopy with bronchoalveolar lavage may have sensitivity about 90%, but likely poses a risk to HCWs. This poses difficulty in ruling-out COVID-19. Bayesian logic dictates that the pre-test probability of disease influences interpretation of test results.

During active epidemic in Wuhan, the prevalence of COVID-19 among patients admitted with suspicion of having viral pneumonia was 60% (3). Assuming sensitivities by RT-PCR for NP swab of 70%, respiratory secretions 70%, and BAL 90%, and specificity >95%, the false negative rate for a single NP swab used to rule out  COVID-19 is 31.6% - that is, 31.6% of patients taken out of isolation based on the negative NP swab result would actually be infected with COVID-19. If a second test, for instance respiratory secretions or another NP swab were performed on all patients whose first test was negative, the false negative rate for the series of tests is 8.8% - likely still not good enough to rule a patient out with confidence. If the second test was a BAL, the false negative rate for the series is 3.5%.

In patients with high pre-test probability of COVID-19, a negative NP swab PCR cannot be safely relied-upon to rule out COVID-19. We recommend bronchial secretions be sent for PCR (in addition to NP swab) in all suspected patients who are intubated. A negative CT scan reduces the probability that a hospitalized patient has COVID-19, but will uncommonly be “negative” in hospitalized patients in whom the diagnosis is considered.

Infection control at home during a surge.

1. Clothes: don’t wear jewelry/watches. Wear hospital-laundered scrubs at work, or take off your work clothes when you get home and throw them in wash machine. Leave your work shoes in your car.
2. Work equipment: Leave stethoscope, pen, googles and other work-related equipment in a locker at work. Wash your hands and ID badge just before getting in your car to leave the hospital. Leave your ID badge in your car while away from work. Don’t bring your personal computer into work unless absolutely necessary.
3. Food: Put a Purell dispenser in front of the refrigerator. Stay out of the kitchen. If have your food prepared for you. Eat on paper plates and then throw them out yourself.
4. Use separate bathroom and sleeping quarters if available.

References

1. Raschke RA, Till SL, Luedy HW. COVID-19 prevention and control recommendations for the ICU. Southwest J Pulm Crit Care. 2020;20(3):95-7. [CrossRef]
2. Cheng VC, Chan JF, To KK, Yuen KY. Clinical management and infection control of SARS: lessons learned. Antiviral Res. 2013 Nov;100(2):407-19. [CrossRef] [PubMed]
3. Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, Tan W. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA. 2020 Mar 11. [Epub ahead of print] [CrossRef] [PubMed]

Cite as: Raschke RA. Further COVID-19 infection control and management recommendations for the ICU. Southwest J Pulm Crit Care. 2020;20(3):100-2. doi: https://doi.org/10.13175/swjpcc020-20 PDF 

COVID-19 Prevention and Control Recommendations for the ICU

Robert A. Raschke, MD¹

Sandra L. Till, DO²

Henry W. Luedy, MD¹

¹HonorHealth Scottsdale Osborn Medical Center

²Banner University Medical Center-Phoenix

Phoenix, AZ USA

Editor’s Note: We are planning on presenting a case of COVID-19 from Osborn as our case of the month for April. The authors felt we should publish preliminary recommendations now early in the COVID-19 pandemic. The recommendations are not necessarily evidence-based but are based on recent experience and published experience with previous coronavirus outbreaks such as SARS.

Background:

• COVID-19 is likely somewhat more infectious than influenza (R value in 2-3 range), and can be transmitted by asymptomatic/presymptomatic persons.
• COVID-19 is already in the community and likely being spread from person to person, Therefore, not all COVID-19 patients will present with a recognized exposure history. Furthermore, fever and pneumonia are not universally present.
• As of this writing, >3,300 healthcare workers have been confirmed infected globally with 6 deaths.
• Testing is currently extremely limited in the US with only a minority of potential cases having been tested at this time. This will likely improve over the next few days to weeks. True incidence likely much higher than reported rates of “confirmed COVID-19”.
• About 15% of patients with confirmed COVID-19 have severe disease and 5% require ICU level care. Mortality rates of approximately 1-2% may be confounded by undertesting, but is currently more than 10 times higher than that of influenza (approx. mortality of 0.05-0.1%) (1).

Infectious disease control issues in the ICU. We recommend droplet, contact and standard precautions when seeing any patient presenting with symptoms of acute upper or lower respiratory tract infection of unknown etiology, regardless whether they meet full CDC criteria for COVID-19 testing. 

Studies during the SARS epidemic showed that intubation, bag-mask ventilation, non-invasive ventilation and tracheostomy procedures were all associated with increased transmission of SARS to healthcare workers (2).

Code arrest. We recommend aerosol, contact and standard precautions and eye protection for all code team members for all codes - regardless of whether COVID-19 is suspected. There is no time in a code to determine the likelihood of the patient having COVID-19, and bag-masking and intubation will aerosolize the patient’s respiratory secretions. A HEPA filter should be placed between the patient and the bag mask to reduce aerosolization of viral particles into the atmosphere.

Elective or semi-elective endotracheal intubation of patients with possible or confirmed COVID-19. If available, powered air-purifying respirators (PAPR) using P100 HEPA filters (filter >99.97% of 0.3 um particles) should be considered over N-95 (filter 95% of 5 um particles) masks during this high-risk procedure based on prior reports of SARS CoV-1 transmission to healthcare workers wearing N95 masks (3). PAPR protects the entire head and neck of the HCW, but requires additional training on donning/duffing.

If unable to wear PAPR, we recommend N95 masks, gowns and gloves, with googles instead of open face shielded masks. Aerosolized particles are more likely to pass around shields into eyes during these high-risk procedures. We also recommend hats and foot protection.

The smallest number of personal required to safely perform the intubation should be present in the room. Fiberoptic laryngoscopy may be preferred over direct laryngoscopy to reduce exposure to aerosolized particles. Once intubated, a HEPA filter should be placed on the exhalational limb of the ventilator.

Non-invasive ventilation and high-flow nasal oxygen. Non-invasive ventilation and high-flow nasal oxygen likely increase the infectivity of COVID-19 by aerosolizing the patient’s respiratory secretions. Consideration should be given to early intubation in patients under investigation or confirmed for COVID-19 (4).

Visitors should not be allowed inside the rooms of such patients except under extreme circumstances and with one-on-one supervision to assure proper use of PPE and handwashing.

Furthermore, we think it is prudent to employ PPE in the rooms of all patients receiving these therapies, since patients with COVID-19 may present atypically (as in the Osborn case). The doors of their rooms should be kept closed, unnecessary traffic in the room reduced, and droplet contact and standard PPE considered, even in patients in whom COVID-19 is not suspected. (This approach has the downside of consuming PPE that might later be in short supply, but has the upside of preserving healthcare workers who also might later be in short supply).

References

1. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020 Feb 24. [Epub ahead of print]. [CrossRef] [PubMed]
2. Tran K, Cimon K, Severn M, Pessoa-Silva CL, Conly J. Aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review. PLoS One. 2012;7(4):e35797. [CrossRef] [PubMed]
3. Cheng VC, Chan JF, To KK, Yuen KY. Clinical management and infection control of SARS: lessons learned. Antiviral Res. 2013 Nov;100(2):407-19. [CrossRef] [PubMed]
4. Zuo MZ, Huang YG, Ma WH, Xue ZG, Zhang JQ, Gong YH, Che L; Chinese Society of Anesthesiology Task Force on Airway Management. Expert recommendations for tracheal intubation in critically ill patients with noval [sic] coronavirus disease 2019. Chin Med Sci J. 2020 Feb 27. [CrossRef] [PubMed]

Cite as: Raschke RA, Till SL, Luedy HW. COVID-19 prevention and control recommendations for the ICU. Southwest J Pulm Crit Care. 2020;20(3):95-7. doi: https://doi.org/10.13175/swjpcc017-20 PDF