The Natural History of a Patient with COVID-19 Pneumonia and Silent Hypoxemia

CASE IN POINT The Natural History of a Patient With COVID-19 Pneumonia and Silent Hypoxemia

Nicholas Hornstein, MD; Gilad M. Jaffe, MD; Kelley Chuang, MD; Jaime Betancourt, MD; and Guy W. Soo Hoo, MD A patient who declined all interventions, including oxygen, and recovered highlights the importance of treating the individual instead of clinical markers and provides a time course for recovery from pneumonia and severe hypoxemia.

Author affiliations n less than a year, COVID-19 has infected benefit in those patients with COVID-19 can be found at the nearly 100 million people worldwide and who require oxygen or mechanical venti- end of the article. caused more than 2 million deaths and lation, but their impact on the progression Correspondence: I Guy Soo Hoo counting. Although the infection fatality of respiratory failure and need for intuba- ([email protected]) rate is estimated to be 1% and the case fa- tion are undetermined. tality rate between 2% and 3%, COVID-19 There also are reports of patients who Fed Pract. 2021;38(4). Published online has had a disproportionate effect on the report no signs of respiratory distress or April 12, 2021 older population and those with comorbidi- dyspnea with their COVID-19 pneumo- doi:10.12788/fp.0100 ties. Some of these findings are mirrored in nia despite profound hypoxemia or high the US Department of Veterans Affairs (VA) oxygen requirements. Various terms, in- population, which has seen a higher case cluding silent hypoxemia or happy hy- fatality rate.1-4 poxia, are descriptive of the demeanor of As a respiratory tract infection, the these patients, and treatment has invari- most dreaded presentation is severe pneu- ably included oxygen.15,16 Nevertheless, monia with acute hypoxemia, which may low oxygen measurements have generally rapidly deteriorate to acute respiratory dis- prompted higher levels of supplemental tress syndrome (ARDS) and respiratory oxygen or more invasive therapies. failure.5-7 This possibility has led to early Treatment rendered may obscure intubation strategies aimed at preempting the trajectory of response, which is im- this rapid deterioration and minimizing portant to understand to better posi- viral exposure to health care workers. In- tion options for invasive therapies and tubation rates have varied widely with ex- other therapeutics. We recently encoun- tremes of 6 to 88%.8,9 tered a patient with a course of illness However, this early intubation strategy that represented the natural history of has waned as some of the rationale behind COVID-19 pneumonia with low oxygen its endorsement has been called into ques- levels (referred to as hypoxemia for con- tion. Early intubation bypasses alternatives sistency) that highlighted several issues of to intubation; high-flow nasal cannula ox- management. ygen, noninvasive ventilation, and awake proning are all effective maneuvers in the Case Presentation appropriate patient.10,11 The use of first- A 62-year-old undomiciled woman with line high-flow nasal cannula oxygen and morbid obesity, prediabetes mellitus, long- noninvasive ventilation has been widely standing schizophrenia, and bipolar disor- reported. Reports of first-line use of high- der presented to our facility for evaluation of flow nasal cannula oxygen has not dem- dry cough and need for tuberculosis clear- onstrated inferior outcomes, nor has the ance for admittance to a shelter. She ap- timing of intubation, suggesting a signifi- peared comfortable and was afebrile with cant portion of patients could benefit from blood pressure 111/74 mm Hg, heart rate a trial of therapy and eventually avoid in- 82 beats per minute. Her respiratory rate tubation.11-14 Other therapies, such as sys- was 18 breaths per minute, but the pulse ox- temic corticosteroids, confer a mortality imetry showed oxygen saturation of 70 to

184 • FEDERAL PRACTITIONER • APRIL 2021 mdedge.com/fedprac 75% on room air at rest. A chest FIGURE 1 Admission and Discharge Chest X-rays X-ray showed bibasilar infiltrates (Figure 1), and a rapid COVID-19 nasopharyngeal polymerase chain reaction (PCR) test returned positive, confirmed by a second PCR test. Baseline inflammatory markers were elevated (Figure 2). In addition, the serum interleukin-6 also was elevated to 66.1 pg/mL (normal < 5.0), erythrocyte sedimenta- tion rate elevated to 69 mm/h, but serum procalcitonin was essen- A, On admission, findings were consistent with COVID-19 pneumonia, including bibasilar infil- tially normal (0.22 ng/mL; normal trates. B, Prior to discharge, improvement of infiltrates can be seen. < 20 ng/mL) as was the serum lac- FIGURE 2 Trends in Peripheral Capillary Oxygen Saturation and tate (1.4 mmol/L). Inflammatory Markers The patient was admitted to the intensive care unit (ICU) for Oxygen Saturation Lactate Dehydrogenase close monitoring in anticipation of the possibility of decompensation 90 400 based on her age, hypoxia, and el- 17 80 U/L 200

evated inflammatory markers. Be- Percent sides a subsequent low-grade fever 70 0 (100.4 oF) and lymphopenia (man- 0 10 20 30 0 10 20 30 ual count 550/uL), she remained Days Days clinically unchanged. Throughout D-Dimer C-Reactive Protein her hospitalization, she maintained 15 20 a persistent psychotic delusion that 10 she did not have COVID-19, refus- 10 ug/mL ing all medical interventions, in- 5 mg/dL cluding a peripheral IV line and 0 0 0 10 20 30 0 10 20 30 supplemental oxygen for the en- Days Days tire duration. Extensive efforts to identify family or a surrogate deci- Ferritin Lymphocytes sion maker were unsuccessful. After 1,500 consultation with Psychiatry, Bio- 2,000 1,000 Ethics, and hospital leadership, ng/mL the patient was deemed to lack 500 cell/uL 1,000 decision-making capacity regard- 0 10 20 30 0 10 20 30 ing treatment or disposition and Days Days was placed on a psychiatric hold. Lowest recorded awake daily peripheral capillary oxygen saturation and inflammatory markers However, since any interventions gathered during hospitalization showed profound hypoxemia and inflammation. Dotted lines indicate upper limits of normal (lower limit in case of lymphocytes). Not included: elevated against her will would require se- interleukin-6 (66.1 pg/mL [normal < 5.0]) and negative procalcitonin. dation, IV access, and potentially increase the risk of nosocomial COVID-19 transmission, she was allowed in the low 80% range, but on day 12, read- to remain untreated and was closely moni- ings were > 90% and remained > 90% for tored for symptoms of worsening respiratory the remainder of her hospitalization. There- failure. fore, shortly after hospital day 12, she was Over the next 2 weeks, her hypoxemia, in- clinically stable for discharge from acute flammatory markers, and the infiltrates on care to a subacute facility, but this required imaging resolved (Figure 2). The lowest daily documentation of the clearance of her viral awake room air pulse oximetry readings are infection. She refused to undergo a subse- reported, initially with consistent readings quent nasopharyngeal swab but allowed an

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TABLE 1 Pulse Oximetry PaO2 Conversion well tolerated in a variety of conditions. A common example are patients with chronic Pulse Partial Pressure of O2 Oximetry, % Under Ideal Circumstances, mm Hg obstructive pulmonary disease. Long-term mortality benefits of continuous supplemen- 90 60 tal oxygen are well established in specific populations, but the threshold for correc- 85 50 tion in the acute setting remains a case-by- case decision. This decision is complex and 80 44 is based on more than an absolute number or the amount of oxygen required to achieve a 75 40 threshold level of oxygenation.

The PaO2/FIO2 (fraction of inspired oxy- oropharyngeal COVID-19 PCR swab, which gen) is a common measure used to address was negative. She remained stable and severity of disease and oxygen requirements. unchanged for the remainder of her It also has been used to define the sever- hospitalization, awaiting identification of ity of ARDS, but the ratio is based on intu- a receiving facility and was able to be dis- bated and mechanically ventilated patients charged to transitional housing on day 38. and may not translate well to those not on assisted ventilation. Treatment with supple- DISCUSSION mental oxygen also involves entrained air The initial reports of COVID-19 pneumo- with associated imprecision in oxygen deliv- nia focused on ARDS and respiratory failure e r y. 18 For this discussion, the patient’s admis-

requiring mechanical ventilation with less sion PaO2/FIO2 on room air would have been emphasis on those with lower severity of ill- between 190 and 260. Coupled with the bi- ness. This was heightened by health care lateral infiltrates on imaging, there was justi- systems that were overwhelmed with large fied concern for progression to severe ARDS. number of patients while faced with lim- Her presentation would have met most of ited supplies and equipment. Given the the epidemiologic criteria used in initial case risk to patients and providers of crash in- finding for severe COVID-19 cases, including

tubations, some recommended early intu- a blood oxygen saturation ≤ 93%, PaO2/FIO2 bation strategies.3 However, the natural < 300 with infiltrates involving close to if not history of COVID-19 pneumonia and the exceeding 50% of the lung. threshold for intubation of these patients With COVID-19 pneumonia, the patho- remain poorly defined despite the cre- logic injury to the alveoli resembles that of ation of prognostic tools.17 This patient’s any viral pneumonia with recruitment of pre- persistent hypoxemia and elevated in- dominantly lymphocytic inflammatory cells flammatory markers certainly met mark- that fill the alveoli, derangements in ventila- ers of disease associated with a high risk of tion/perfusion mismatch as the core mech- progression. anism of hypoxemia with interstitial edema The greatest concern would have been her and shuntlike physiology developing at the level of hypoxemia. Acceptable thresholds extremes of involvement. In later stages, the of hypoxemia vary, but general consensus histologic appearance is similar to ARDS, in- would classify pulse oximetry < 90% as hy- cluding hyaline membrane formation and poxemia and a threshold for administering thickened alveolar septa with perivascular supplemental oxygen. It is important to rec- lymphocytic-plasmocytic infiltration. In ad- ognize how pulse oximetry readings translate dition, there also are findings of organizing

to partial pressure of oxygen (PaO2) mea- pneumonia with fibroblastic proliferation, surements (Table 1). Pulse oximetry readings thrombosis, and diffuse alveolar damage, a

of 90% corresponds to a PaO2 readings of constellation of findings similar to that seen 60 mm Hg in ideal conditions without the in- in the latter stages of ARDS.2

fluence of acidosis, PaCO2, or temperature. Although these histologic findings re- While lower readings are of concern, these semble ARDS, many patients with respira- do not represent absolute indications for as- tory failure due to COVID-19 have a different sisted ventilatory support as lower levels are physiologic profile compared with those with

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typical ARDS, with the most striking finding TABLE 2 Considerations in Patients With COVID-19 of lungs with low elastance or high compli- Pneumonia and Silent Hypoxemia ance. From the critical care standpoint, this meant that the lungs were relatively easy to Conditions Descriptions ventilate with lower peak airway and pla- Oxyhemoglobin • Shifts to the right during fever, acidosis teau pressures and low driving pressures. dissociation • Shifts to the left with alkalosis and hypocapnia This condition suggested that there was rel- curve atively less lung that could be recruited with positive end expiratory pressure; therefore, Mechanisms of • Ventilation-perfusion mismatch (pneumonia, microthrombi) a somewhat different entity from that as- hypoxemia • Shunt (disordered vasoregulation) sociated with ARDS.19 These findings were • Diffusion impairment (alveolar injury and damage) often noted early in the course of respiratory Histology of • Diffuse alveolar damage failure, and although there is debate about COVID-19 • Interstitial edema whether this represents a different pheno- pneumonia • Organizing pneumonia type or timepoint in the spectrum of disease, • Vasculature with microthrombi it clearly represents a subset that is dis- tinct from that which had been previously Blunted ventilatory • Decreased due to age response to O2 • Decreased due to comorbidities (diabetes mellitus, encountered. chronic obstructive pulmonary disease) On the other hand, the clinical features • Suppressed by hypocapnia seen in those patients with COVID-19 pneumonia who progressed to advanced respira- COVID-19 • Early: normal peak airway, plateau, driving pressures pneumonia • Early: normal lung compliance tory failure were essentially indistinguishable physiology • Late: increased peak airway, plateau, driving pressures from those patients with traditional ARDS. Other explanations for this respiratory failure Preintubation • Supplemental oxygen have included a disrupted vasoregulatory re- treatment of • High-flow nasal cannula oxygen sponse to hypoxemia with failed hypoxic va- hypoxemia • Noninvasive ventilation soconstriction, intravascular microthrombi, • Awake prone positioning and impaired diffusion, all contributing to impaired gas exchange and hypoxemia.19-21 try measurement and shifts in the oxyhemo- This can lead to shuntlike conditions that nei- globin dissociation curve. However, this is ther respond well to supplemental oxygen more pertinent for those with mild disease as nor manifest the type of physiologic response the severity of hypoxemia in severe pneumo- seen with other causes of hypoxemia. nia is beyond what can be attributed to tech- The severity of hypoxemia manifested nical issues. by this patient may have elicited additional More important, the ventilatory re- findings of respiratory distress, such as dys- sponse curve to hypoxemia may not pnea and tachypnea. However, in patients be normal for some patients, blunted by with severe COVID-19 pneumonia, dyspnea as much as 50% in older patients, espe- was not a universal finding, reported in the cially in those with diabetes mellitus.7,25,26 20 to 60% range of cohorts, higher in those In addition, the ventilatory response var- with ARDS and mechanical ventilation, al- ies widely even among normal individu- though some report near universal dyspnea als. This would translate to lower levels of in their series.1,4,8,22,23 Tachypnea is another minute ventilation (less tachypnea or re- symptom of interest. Using a threshold of spiratory effort) with hypoxemia. Hy- > 24 breaths/min, tachypnea was noted in pocapnic hypoxemia also blunts the 16 to 29% of patients with a much greater ventilatory response to hypoxemia. Subjects proportion (63%) in nonsurvivors.6,24 Several do not increase their minute ventilation

explanations have been proposed for the dis- if the PaCO2 remains low despite oxygen cordance between the presence and severity desaturation to < 70%, especially if PaCO2 of hypoxemia and lack of symptoms of dys- < 30 mm Hg or alternatively, increases in pnea and tachypnea. It is important to recog- minute ventilation are not seen until the 27 nize that misclassification of the severity of PaCO2 exceeds 39 mm Hg. Both scenar- hypoxemia can occur due to technical issues ios occur in those with COVID-19 pneumo- and potential errors involving pulse oxime- nia and provide another explanation for the

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absence of respiratory symptoms or signs of pneumonia that has not previously been well respiratory distress in some patients. appreciated. It is important to recognize that The observation of more compliant lungs recovery occurred over 2 weeks. This is close may help in the understanding of the variable to the observed and expected time for recov- presentation of these patients. Compliant ery that has been reported for those with se- lungs do not require the increased pressure vere COVID-19 pneumonia. needed to achieve a specific tidal vol- ume that, in turn, may increase the work of CONCLUSIONS breathing. This may add to the explanation Since the emergence of the COVID-19, evi- of seemingly paradoxical silent hypoxemia dence has accumulated for the benefit of sev- in those patients where the combination of eral adjunctive therapies in the treatment of a blunted ventilatory response, hypocapnia, this type of pneumonia, with corticosteroids shunt physiology, and normal respiratory sys- providing a mortality benefit. Although un- tem compliance is represented by the absence known whether this patient’s experience can of increased breathing effort despite severe be generalized to others or whether it rep- hypoxemia. resents her unique response, this case pro- If not for the patient’s refusal of medical vides another perspective for comparison of services, this patient quite possibly would treatments and reinforces the need for pro- have been intubated due to hypoxemia and spective, randomized clinical trials to estab- health care providers’ concern for her risk of lish treatment efficacy. The exact nature of deterioration. Reported intubation and me- silent hypoxemia of COVID-19 remains in- chanical ventilation rates have varied widely completely understood; however, this case from extremes of from < 5 to 88% in severely highlights the importance of treating the in- ill patients.9,22 About 75% will need oxygen, dividual instead of clinical markers and but many can be treated and recover with- provides a time course for recovery from out the need for intubation and mechanical pneumonia and severe hypoxemia that oc- ventilation. curs without oxygen or any other treatment As previously mentioned, options for over about 2 weeks. treatment include standard and high-flow ox- Author affiliations ygen delivery, noninvasive ventilation, and Nicholas Hornstein is a Resident in the Department of Medi- awake prone ventilation. Their role in patient cine, Division of General Internal Medicine, and Gilad Jaffe is a management has been recently outlined, and Fellow in the Department of Medicine, Division of Pulmonary, instead of an early intubation strategy, repre- Critical Care and Sleep, both at Ronald Reagan-UCLA Medi- cal Center. Kelley Chuang is a Hospitalist in the Department sents gradual escalation of support that may of Medicine; Jaime Betancourt is the Director, Pulmonary be sufficient to treat hypoxemia and avoid Physiology Laboratory and Oxygen Program in the Pulmonary, the need for intubation and mechanical ven- Critical Care, and Sleep Section; and Guy Soo Hoo is the Chief, Pulmonary, Critical Care and Sleep Section; all at the tilation (Table 2). Veterans Affairs Greater Los Angeles Healthcare System. Kelley In addition, the patient’s hospital course Chuang is an Assistant Clinical Professor, Jaime Betancourt is was notable for the decline in known mark- an Associate Clinical Professor, and Guy Soo Hoo is a Clinical ers of active inflammation that mirrored the Professor, all at the David Geffen School of Medicine, Univer- resolution of her hypoxemia and pneumo- sity of California Los Angeles. nia. This included elevated lactate dehy- Author disclosures drogenase, D-dimer, ferritin, and C-reactive The authors report no actual or potential conflicts of interest protein with all but the latter rising and de- Disclaimer creasing over 2 weeks. These findings pro- The opinions expressed herein are those of the authors and do vide additional information of the time for not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any recovery and supports the use of these mark- of its agencies. This article may discuss unlabeled or inves- ers to monitor the course of pneumonia. tigational use of certain drugs. Please review the complete The patient declined all intervention, in- prescribing information for specific drugs or drug combina- tions—including indications, contraindications, warnings, and cluding oxygen, and recovered to her pre- adverse effects—before administering pharmacologic therapy sumed prehospitalization condition. This to patients. experiment of nature due to unique circum- References stances may shed light on the natural time 1. Ioannou GN, Locke E, Green P, et al. Risk factors course of untreated hypoxemic COVID-19 for hospitalization, mechanical ventilation, or death

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