Covid Dodges 2 NPSs

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Here is a paper from our own two Bills that supports “Clinical Covid is Covid. Full stop.

Crazy paving – a CT chest appearance where the combination of septal thickening and alveolar ground-glass opacity creates a pattern that mimics paving. The sign is classically described in pulmonary alveolar proteinosis but can be caused by many other lung pathologies.

Diagnosis of COVID-19 by Bronchoalveolar Lavage after Two Negative Nasophayngeal Swabs


This case report highlights the diagnostic limitations of nasopharyngeal swabs in diagnosingCOVID-19. This patient had a positive travel history, typical symptoms (fever, dry cough, dyspnea) and two negative nasopharyngeal swabs (NPS). He deteriorated clinically and required intubation. After intubation, bronchoalveolar lavage was used to sample the lower respiratory tract, which confirmed the diagnosis of COVID-19. This case demonstrates the diagnostic limitation of reliance solely on nasopharyngeal swab PCR alone for the diagnosis of COVID-19. NPS tests may result in false negatives with incorrect sampling technique or if the sampling is done while the upper tract viral load is low, such as very early or late during the illness course. During this pandemic, we posit that clinicians should maintain a high degree of suspicion based on supportive clinical findings despite negative PCR testing as this has implications for hospital infection control procedures.


COVID-19 is a pandemic driven by a rapidly spreading, severe respiratory illness caused by a novel coronavirus: SARS-CoV2.

Polymerase chain reaction (PCR) for SARS-CoV2 using nasopharyngeal swabs (NPS) samples is the current standard for diagnosis.1 Assessment of the World Health Organization’s PCR assays demonstrated high specificity (100%), and sensitivity of 61–68%, which increases to
71–79% with repeated testing.2 In one study, 33% of suspected COVID-19 patients with negative PCR testing had computed tomography (CT) findings consistent with COVID-19.3 Others concluded COVID-19 could not be reliably diagnosed using PCR alone, given its low
sensitivity,4 which is affected by the time of sampling (i.e., when viral shedding occurs), correct sampling technique and assays with a poor limit of detection. In an analysis of site sampling, lower respiratory tract samples were positive more often than NPS. However, it is biased towards severely ill, intubated patients, where endotracheal tube sampling is feasible. 1

There is only one published report of COVID-19
diagnosed with bronchoalveolar lavage (BAL) after numerous negative NPS.5 We report what we believe is the first case in North America.


To alert clinicians to maintain a high suspicion for COVID-19 in the appropriate clinical context, despite recurrent negative NPS testing and to highlight potential difficulties in removing isolation precautions in the intensive care unit

Case Study

A 54-year-old male with a history of gout travelled from Canada to the United States from February 29th-March 1st, 2020. Twelve days after, he developed persistent fevers, myalgias, dyspnea, a dry cough, nausea, and vomiting. On
symptom day 5, his family physician ordered a chest x-ray, which was normal. Treatment with amoxicillin-clavulanate offered no improvement. He presented to the emergency department on symptom day 7.

At presentation, he was afebrile; his oxygen saturation was 93% on 2 L of oxygen via nasal prongs. Chest x-ray demonstrated new bilateral, peripheral airspace opacities. Initial blood work demonstrated lymphopenia (0.6×109/L),
hyponatremia (134 mmol/L), normal liver enzymes and elevated inflammatory markers (c-reactive protein 137 mg/L, lactate dehydrogenase 965 IU/L). Urine legionella antigen and NPS for SARS-CoV2, influenza A, influenza B,
respiratory syncytial virus, metapneumovirus,
parainfluenza types 1 and 3, adenovirus, rhinovirus and enterovirus were sent. He was admitted to the medical ward and started on ceftriaxone and azithromycin for possible community-acquired pneumonia.

On symptom day 8, he was transferred to the ICU for hypoxemic respiratory failure, initially managed with a high-flow nasal cannula (50 L/min, FiO2 80%). The initial NPS was negative for all respiratory viruses, including SARS-CoV2. Another swab was sent given the high index
of suspicion. By symptom day 10, he was intubated. Repeat NPS was negative.

Subsequent laboratory investigations demonstrated persistent lymphopenia, transaminitis (aspartateaminotransferase 63 IU/L, alanine aminotransferase 51 IU/L, alkaline phophate level 144 IU/L, gamma-glutamyl transferase 310I U/L), hyperbilirubinemia 40 umol/L, c-reactive protein 299 mg/L, lactate dehydrogenase 972 IU/L, and ferritin 1020 ug/L. A workup for infectious, malignant and autoimmune etiologies for acute respiratory distress syndrome were all negative.

An abdominal/pelvic computed tomography demonstrated no intra-abdominal abnormalities but identified lung findings consistent with COVID-19, including bilateral pleural effusions, atelectasis vs consolidation, including crazy paving (figure 1). Subsequently, bronchoscopy and BAL was performed. BAL was positive for SARS-CoV2.

Figure 1. Lower lung zones captured on computed tomography of the abdomen/pelvis
demonstrating bilateral pleural effusions, atelectasis vs. consolidation, and crazy-paving.


Our case demonstrates that despite negative NPS for SARS-CoV2, clinicians should maintain a high degree of suspicion, given the patient’s history, clinical trajectory, and CT findings. Our polymerase chain reaction assay has excellent sensitivity (95%) and specificity (100%) for SARS-CoV2. This, however, relies on adequate viral load and proper sampling techniques. We believe our patient’s nasopharyngeal viral load likely resolved by the time of NPS sampling, explaining the false-negative results.

Given the consequences of false-negative tests, a multimodal approach to the diagnosis of COVID-19 is favourable, especially in critically ill patients.

While BAL confirmed the diagnosis and assessed for comorbidities, it is an aerosolizing procedure and should be performed at the clinician’s discretion. In intubated patients, endotracheal tube aspiration offers a non-aerosol generating alternative for sampling the lower airways.

Therefore, when the clinical suspicion for COVID-19 remains high despite negative NPS testing, infection control precautions should remain for patient and healthcare provider safety. Furthermore, NPS results may not be reliably used as a test of cure in the context of previously false-negative results. This has implications on resource allocation and must be considered when removing isolation precautions.


All authors contributed equally to this work. The authors disclose no conflicts of interest.

Figure  1.

Figure 1. Lower lung zones captured on computed tomography of the abdomen/pelvis
demonstrating bilateral pleural effusions, atelectasis vs. consolidation, and crazy-paving.


  1. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA 2020 Mar 11;
  2. Yam WC, Chan KH, Poon LLM, et al. Evaluation of reverse transcription-PCR assays for rapid diagnosis of severe acute respiratory syndrome associated with a novel coronavirus. J Clin Microbiol 2003 Oct;41(10):4521–4.
  3. Ai T, Yang Z, Hou H, et al. Correlation of chest CT and rt-pcr testing in coronavirus disease 2019 (COVID-19) in China: A report of 1014 cases. Radiology 2020 Feb 26;200642.
  4. Xie C, Jiang L, Huang G, et al. Comparison of different samples for 2019 novel coronavirus detection by nucleic acid amplification tests. Int J Infect Dis IJID Off Publ Int Soc Infect Dis 2020 Feb 27;93:264–7.
  5. Ruan Z-R, Gong P, Han W, et al. A case of 2019 novel coronavirus infected pneumonia with twice negative 2019-nCoV nucleic acid testing within 8 days. Chin Med J (Engl) 2020 Mar 5;1.

L and H Covid Phenotypes

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The Surviving Sepsis Campaign panel (ahead of print, DOI: 10.1007/s00134-020-06022-5) recently recommended that “mechanically ventilated patients with COVID-19 should be managed similarly to other patients with acute respiratory failure in the ICU.”

Yet, COVID-19 pneumonia [1], despite falling in most of the circumstances under the Berlin definition of ARDS [2], is a specific disease, whose distinctive features are severe hypoxemia often associated with near normal respiratory system compliance (more than 50% of the 150 patients measured by the authors and further confirmed by several colleagues in Northern Italy). This remarkable combination is almost never seen in severe ARDS. These severely hypoxemic patients despite sharing a single etiology (SARS-CoV-2) may present quite differently from one another: normally breathing (“silent” hypoxemia) or remarkably dyspneic; quite responsive to nitric oxide or not; deeply hypocapnic or normo/hypercapnic; and either responsive to prone position or not. Therefore, the same disease actually presents itself with impressive non-uniformity.

Based on detailed observation of several cases and discussions with colleagues treating these patients, we hypothesize that the different COVID-19 patterns found at presentation in the emergency department depend on the interaction between three factors:

  1. the severity of the infection, the host response, physiological reserve and comorbidities;
  2. the ventilatory responsiveness of the patient to hypoxemia;
  3. the time elapsed between the onset of the disease and the observation in the hospital.

The interaction between these factors leads to the development of a time-related disease spectrum within two primary “phenotypes”: Type L, characterized by Low elastance (i.e., high compliance), Low ventilation to perfusion ratio, Low lung weight and Low recruitability and Type H, characterized by High elastance, High right-to-left shunt, High lung weight and High recruitability.

COVID Pneumonia, Type L

At the beginning, COVID-19 pneumonia presents with the following characteristics:

  • Low elastance: the nearly normal compliance indicates that the amount of gas in the lung is nearly normal [3].
  • Low ventilation to perfusion (VA/Q) ratio: since the gas volume is nearly normal, hypoxemia may be best explained by the loss of regulation of perfusion and by loss of hypoxic vasoconstriction. Accordingly, at this stage, the pulmonary artery pressure, should be near normal.
  • Low lung weight: Only ground-glass densities are present on CT scan, primarily located subpleurally and along the lung fissures. Consequently, lung weight is only moderately increased.
  • Low lung recruitability: the amount of non-aerated tissue is very low, consequently the recruitability is low [4].

To conceptualize these phenomena, we hypothesize the following sequence of events: the viral infection leads to a modest local subpleural interstitial edema (ground-glass lesions) particularly located at the interfaces between lung structures with different elastic properties, where stress and strain are concentrated [5].

Vasoplegia accounts for severe hypoxemia. The normal response to hypoxemia is to increase minute ventilation, primarily by increasing the tidal volume [6] (up to 15-20 ml/kg), which is associated with a more negative intrathoracic inspiratory pressure. Undetermined factors other than hypoxemia, markedly stimulate, in these patients, the respiratory drive. The near normal compliance, however, explains why some of the patients present without dyspnea as the patient inhales the volume he expects. This increase in minute ventilation leads to a decrease in PaCO2.

The evolution of the disease: transitioning between phenotypes

The Type L patients may remain unchanging for a period and then improve or worsen the possible key feature which determines the evolution of the disease – other than the severity of the disease itself, is the depth of the negative intrathoracic pressure associated with the increased tidal volume in spontaneous breathing. Indeed, the combination of a negative inspiratory intrathoracic pressure and increased lung permeability due to inflammation, results in interstitial lung edema. This phenomenon, initially described by Barach in 1938 [7] and Mascheroni in 1988 [8] both in an experimental setting, has been recently recognized as the leading cause of Patient – Self Inflicted Lung Injury (P-SILI) [9].

Over time, the increased edema increases lung weight, superimposed pressure, and dependent atelectasis. When lung edema reaches a certain magnitude, the gas volume in the lung decreases , and the tidal volumes generated for a given inspiratory pressure decrease [10]. At this stage, dyspnea develops, which in turn leads to worsening P-SILI. The transition from Type L to Type H may be due to the evolution of the COVID-19 pneumonia on one hand and the injury attributable to high-stress ventilation on the other.

COVID Pneumonia, Type H

The Type H patient

  • High elastance: The decrease of gas volume due to increased edema accounts for the increased lung elastance.
  • High right-to-left shunt: This is due to the fraction of cardiac output perfusing the non-aerated tissue which develops in the dependent lung regions due to the increased edema and superimposed pressure.
  • High lung weight: Quantitative analysis of the CT scan shows a remarkable increase in lung weight (> 1.5 kg), on the order of magnitude of severe ARDS [11].
  • High lung recruitability: The increased amount of non-aerated tissue is associated, as in severe ARDS, with increased recruitability [12].

The Type H pattern, 20 – 30% of patients in our series, fully fits the severe ARDS criteria: hypoxemia, bilateral infiltrates, decreased the respiratory system compliance, increased lung weight and potential for recruitment.

Figure 1 summarizes the time course we described. In Panel A, we show the  CT in spontaneous breathing of a Type L patient at admission and, in Panel B, its transition in Type H after 7 days of non invasive support. As shown, a similar degree of hypoxemia was associated to different patterns in lung imaging.

Respiratory treatment

Given this conceptual model, it follows that the respiratory treatment offered to Type L and Type H patients must be different. The proposed treatment is consistent with what observed in COVID-19, even though the overwhelming number of patients seen in this pandemic may limit its wide applicability.

  1. The first step to reverse hypoxemia is through an increase in FiO2 to which the Type L patient respond wells, particularly if not yet breathless.
  2. In Type L patients with dyspnea, several non-invasive options are available: High Flow Nasal Cannula (HFNC), Continuous Positive Airway Pressure (CPAP) or Non Invasive Ventilation (NIV). At this stage the measurement (or the estimation) of the inspiratory esophageal pressure swings is crucial [13]. In the absence of the esophageal manometry, surrogate measures of work of breathing, such as the swings of central venous pressure [14], or clinical detection of excessive inspiratory effort should be assessed. In intubated patients the P0.1 and P occlusion should also be determined. High PEEP, in some patients, may decrease the pleural pressure swings and stop the vicious cycle that exacerbates lung injury. However, high PEEP in patients with normal compliance may have detrimental effects on hemodynamics. In any case, non-invasive options are questionable, as they may be associated with high failure rates and delayed intubation, in a disease which typically lasts several weeks.
  3. The magnitude of inspiratory pleural pressures swings may determine the transition from the Type L to the Type H phenotype. As esophageal pressure swings increase from 5-10 cmH2O – which are generally well tolerated – to above 15 cmH2O, the risk of lung injury increases and therefore intubation should be performed as soon as possible.
  4. Once intubated and deeply sedated, the Type L patients, if hypercapnic, can be ventilated with volumes greater than 6 ml/kg (up to 8-9 ml/kg). as the high compliance results in tolerable strain without the risk of VILI. Prone positioning should be used only as a rescue maneuver, as the lung conditions are “too good” for the prone position effectiveness, which is based on improved stress and strain redistribution. The PEEP should be reduced to 8-10 cmH2O, given that the recruitability is low and the risk of hemodynamic failure increases at higher levels. An early intubation may avert the transition to Type H phenotype.
  5. Type H patients, should be treated as severe ARDS, including higher PEEP, if compatible with hemodynamics, prone positioning and extracorporeal support.


In conclusion, Type L and Type H patients are best identified by CT scan and are affected by different pathophysiological mechanisms. If not available, signs which are implicit in Type L and Type H definition could be used as surrogates: respiratory system elastance and recruitability. Understanding the correct pathophysiology is crucial to establishing the basis for appropriate treatment.


  1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W, China Novel Coronavirus I, Research T, (2020) A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med 382: 727-733
  2. Force ARDSDT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS, (2012) Acute respiratory distress syndrome: the Berlin Definition. JAMA
  3. Gattinoni L, Pesenti A, Avalli L, Rossi F, Bombino M, (1987) Pressure-volume curve of total respiratory system in acute respiratory failure. Computed tomographic scan study. The American review of respiratory disease
  4. Gattinoni L, Caironi P, Cressoni M, Chiumello D, Ranieri VM, Quintel M, Russo S, Patroniti N, Cornejo R, Bugedo G, (2006) Lung recruitment in patients with the acute respiratory distress syndrome. The New England journal of medicine
  5. Cressoni M, Cadringher P, Chiurazzi C, Amini M, Gallazzi E, Marino A, Brioni M, Carlesso E, Chiumello D, Quintel M, Bugedo G, Gattinoni L, (2014) Lung inhomogeneity in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 189: 149-158
  6. Vaporidi K, Akoumianaki E, Telias I, Goligher EC, Brochard L, Georgopoulos D, (2020) Respiratory Drive in Critically Ill Patients. Pathophysiology and Clinical Implications. Am J Respir Crit Care Med 201: 20-32
  7. Barach Al, Martin J, Eckman M, (1938) Positive Pressure Respiration And Its Application To The Treatment Of Acute Pulmonary Edema. Annals of Internal Medicine 12: 754-795
  8. Mascheroni D, Kolobow T, Fumagalli R, Moretti MP, Chen V, Buckhold D, (1988) Acute respiratory failure following pharmacologically induced hyperventilation: an experimental animal study. Intensive Care Med 15: 8-14
  9. Brochard L, Slutsky A, Pesenti A, (2017) Mechanical Ventilation to Minimize Progression of Lung Injury in Acute Respiratory Failure. Am J Respir Crit Care Med 195: 438-442
  10. Pelosi P, D’Andrea L, Vitale G, Pesenti A, Gattinoni L, (1994) Vertical gradient of regional lung inflation in adult respiratory distress syndrome. Am J Respir Crit Care Med 149: 8-13
  11. Maiolo G, Collino F, Vasques F, Rapetti F, Tonetti T, Romitti F, Cressoni M, Chiumello D, Moerer O, Herrmann P, Friede T, Quintel M, Gattinoni L, (2018) Reclassifying acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine 197: 1586-1595
  12. Gattinoni L, Caironi P, Cressoni M, Chiumello D, Ranieri VM, Quintel M, Russo S, Patroniti N, Cornejo R, Bugedo G, (2006) Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med 354: 1775-1786
  13. Gattinoni L, Giosa L, Bonifazi M, Pasticci I, Busana M, Macri M, Romitti F, Vassalli F, Quintel M, (2019) Targeting transpulmonary pressure to prevent ventilator-induced lung injury. Expert Rev Respir Med 13: 737-746
  14. Walling PT, Savege TM, (1976) A comparison of oesophageal and central venous pressures in the measurement of transpulmonary pressure change. Br J Anaesth 48: 475-479

Figure 1

Panel A: CT scan acquired during spontaneous breathing. The cumulative distribution of the CT numberis shifted to the left (well aerated compartments), being the 0 to -100 HU compartment, the non-aerated tissue virtually 0. Indeed, the total lung tissue weight was 1108 g, 7.8% of which was not aerated and the gas volume was 4228 ml. Patient receiving oxygen with Venturi mask, inspired oxygen fraction of 0.8.

Panel B: CT acquired during mechanical ventilation at end-expiratory pressure at 5 cmH2O of PEEP. Thecumulative distribution of the CT scan is shifted to the right (non-aerated compartments) while the left compartments are greatly reduced. Indeed, the total lung tissue weight was 2744 g, 54% of which was not aerated and the gas volume was 1360 ml. The patient was ventilated in Volume Controlled mode, 7.8 ml/kg of tidal volume, respiratory rate of 20 breaths per minute, inspired oxygen fraction of 0.7