Re: Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study - The BMJ

Posted: 26 Mar 2020 12:00 AM PDT

Dear Editor

This is an interesting article from a Paediatric Surgeon's perspective.

We would like to highlight the possibility of histopathology similarity between the critically ill SARS-Cov-2 patients to moribund infants with a congenital diaphragmatic hernia (CDH). Hopefully, this may lead to a possible lead upon clinical management of the acutely ill SARS-CoV-2 patients.

A) CLINICAL COURSE SIMILARITY:

The novel coronavirus disease 2019 (COVID-19) can induce acute respiratory distress syndrome (ARDS), which can progress to refractory pulmonary failure. The mortality of critically ill patients with SARS-CoV-2 pneumonia is considerable. The survival time of the non-survivors is likely to be within 1–2 weeks after ICU admission. [1] In such cases, extracorporeal membrane oxygenation (ECMO) may be considered as rescue therapy.

Similarly, in the immediate postnatal phase of some CDH moribund infants, there is a short period of better oxygenation referred to as the "honeymoon" period. [2] However, progressive deterioration in oxygenation is commonly observed due to a combination of pulmonary arterial hypertension, right ventricular hypertrophy and/or failure, and left ventricular hypoplasia with pulmonary venous hypertension results in severe Persistent pulmonary hypertension of the newborn (PPHN) unresponsive to conventional management following birth. [2]

Treatment after birth requires all the refinements of critical care including extracorporeal membrane oxygenation (ECMO) prior to surgical correction.

B) HISTOPATHOLOGIC SIMILARITY:

Animal models of CDH have demonstrated that in utero compression of developing fetal lungs by herniated abdominal viscera impairs pulmonary growth and maturation, resulting in pulmonary hypoplasia, which can be quantified by histologic, biochemical, and pulmonary morphometric techniques. Whatever its cause, pulmonary hypoplasia, which usually is a bilateral process, even in unilateral CDH, results in alveolar hypoplasia and a distinctly abnormal pulmonary vascular bed. Arterial branches are reduced, and there is a medial thickening in the small preacinar and intra-acinar arterioles. The physiologic consequence of this abnormality in pulmonary vasculature is an increase in pulmonary vascular resistance, which contributes to the development of persistent pulmonary hypertension, arguably the principal determinant of mortality in CDH. Another contributing factor appears to be a hyperreactivity to known stimuli of pulmonary vasoconstriction, including hypoxia, acidosis, hypothermia, and stress.

Similarly, the microscopic findings in SARS-CoV-2 patients included diffuse alveolar damage with exudates. The inflammation was predominantly lymphocytic, and multinucleated giant cells were seen alongside large atypical pneumocytes, although no definitive viral inclusions were noted.

POSSIBLE INFERENCES:

ECMO IN CDH moribund Infants provides a means of maintaining oxygen delivery only temporarily, and its salvage rate depends on the reversibility of the pathologic factors that led to respiratory failure within the time frame that ECMO can be used. Although the pulmonary hypoplasia associated with CDH can be "outgrown", the time required for this adaptive process often exceeds that provided by ECMO bypass. This accounts for the significant differences in survival observed between patients who have CDH and those who have more rapidly reversible causes of respiratory failure, including PPHN, meconium aspiration syndrome, and sepsis.

However, that may not be the case in critically ill SARS-CoV-2. Hopefully, the timely use of ECMO would lead to better clinical outcomes in critically ill SARS-CoV-2 patients as compared to CDH infants. More so considering that in the study of ECMO for ARDS in patients with Middle East Respiratory Syndrome Coronavirus (MERS-CoV), a similar coronavirus disease that emerged in 2012, a significant decrease of in-hospital mortality rate and length of intensive care unit (ICU) stay was found in patients treated with ECMO compared to those managed with conventional therapy.

References:
1. Brandon Michael Henry, Giuseppe Lippi. Poor survival with extracorporeal membrane oxygenation in acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19): Pooled analysis of early reports. J. Crit Care 2020 Apr 1 doi: 10.1016/j.jcrc.2020.03.011 [Epub ahead of print]

2. Nair J, Lakshminrusimha S. Update on PPHN: mechanisms and treatment. Semin Perinatol. 2014;38(2):78–91.

Ambrisentan and Tadalafil Combination Therapy Appropriate for CTD-PAH - Pulmonology Advisor

Posted: 06 Apr 2020 12:00 AM PDT

Combination therapy is appropriate for patients with typical pulmonary arterial hypertension (PAH) categorized as low and intermediate risk at baseline, while high-risk patients could possibly be considered for more advanced therapy, according to study results published in the Annals of the Rheumatic Diseases.¹

Connective tissue disease-associated PAH (CTD-PAH) is the second most common etiology of PAH and has the most severe disease characteristics and the highest mortality of all PAH subgroups.¹ The Ambrisentan and Tadalafil in Patients with PAH study (AMBITION; ClinicalTrials.gov Identifier: NCT01178073) demonstrated that patients with CTD-PAH benefited from initial combination therapy with ambrisentan plus tadalafil compared with either agent alone when patients with risk factors for left heart disease were excluded.²

Researchers conducted a post hoc subgroup analysis of the AMBITION modified intention-to-treat CTD-PAH population to assess the relationship between baseline characteristics and outcome and evaluated the utility of an abbreviated, 3-parameter noninvasive risk stratification score in predicting outcomes in patients with CTD-PAH.¹

This analysis included 216 patients (combination therapy, n=117; monotherapy, n=99), and they found that the risk for clinical failure was lower with combination therapy vs monotherapy, specifically 51.7% lower in the CTD-PAH population (hazard ratio [HR], 0.48; 95% CI, 0.28%-0.81%) and 53.7% in the systemic sclerosis-PAH population (HR, 0.46; 95% CI, 0.24%-0.89%). The risk for clinical failure was lower with combination therapy vs monotherapy in the baseline low-risk group, baseline intermediate-risk group, and in the week 16 low-risk group.

"In patients with CTD-PAH, the risk of clinical failure was lower with combination therapy versus monotherapy, particularly in those with baseline hemodynamic parameters characteristic of typical PAH, without features of left heart disease and/or restrictive lung disease,"¹ the investigators wrote. "A simplified risk stratification score at baseline may help inform disease management in patients with CTD-PAH, but further studies with larger patient populations are required."

Disclosure: This clinical trial was supported by GlaxoSmithKline and Gilead Sciences, Inc. Please see the original reference for a full list of authors' disclosures.

References

1. Kuwana M, Blair C, Takahashi T, Langley J, Coghlan JG. Initial combination therapy of ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) in the modified intention-to-treat population of the AMBITION study: post hoc analysis [published online March 11, 2020]. Ann Rheum Dis. doi:10.1136/annrheumdis-2019-216274

2. Galiè N, Barberà JA, Frost AE, et al; for the AMBITION Investigators. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373:834-844.

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