SARS-CoV-2 can be a causal factor of Phrenic Neuropathy and Diaphragmatic Dysfunction


Neuropathy has been described as one of the neurological manifestations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in coronavirus disease 2019 (COVID-19).

SARS-CoV-2 infection can cause several neurological manifestations, including neuropathies [1]; however, it represents an important problem due to its acute consequences that can significantly increase mortality. Inflammatory olfactory neuropathy [2], motor peripheral neuropathy [3] and neuromuscular involvement in COVID-19 critically ill patients [4] are some examples of the multiple reports from around the world of the ability of SARS-CoV-2 to generate damage to the peripheral nervous system.

On the other hand, the main causes of hypoxemia in patients diagnosed with COVID-19 are due to the damage caused by the viral infection in the lung parenchyma.

In the present series of cases, we expose the neuropathic damage that SARS-CoV-2 can generate on the neural circuits responsible for the innervation of the main respiratory muscle, the diaphragm.

Currently, there are several reports of neuromuscular disease due to COVID-19 [5]; however, documented cases of diaphragm neuropathy are very rare, causing rapid deterioration of respiratory mechanics in COVID-19 patients [6]. Borroni et al. reported two COVID-19 patients with focal diaphragmatic myoclonus (DM) [7].

With the present observation, we report four cases of diaphragmatic dysfunction due to phrenic nerve (PN) neuropathy, as a neurological acute complication of SARS-CoV-2 infection.

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The most common clinical presentation of severe COVID-19 is acute respiratory failure consistent with acute respiratory distress syndrome (ARDS) [8]. Many patients hospitalized with severe pneumonia due to COVID-19 show hypoxemia without clinical signs of dyspnea, a condition which has been coined ‘happy hypoxemia’.

In a limited number of patients, a sudden deterioration occurs during the course of illness, with an increase in oxygen demand when fatigue and dyspnea set in. We hypothesized that dysfunction of the diaphragm could be a contributing factor in the clinical course of patients requiring admission to the ICU [9].

In this report, we described the cases of four patients with COVID-19 diagnosis who presented with acute diaphragmatic neuromuscular dysfunction secondary to phrenic neuropathy. COVID-19 patients with PN damage represent a therapeutic challenge since they have high oxygen requirements due to the affection of VM secondary to neuromuscular damage, in addition to the damage of the lung parenchyma that causes viral pneumonia.

MV dysfunction causes higher supplemental oxygen requirements, associated with a greater demand for volume and concentration to maintain SpO2; increasing the risk of IV, prolonged stay in the intensive respiratory care unit, predisposing to other nosocomial pneumonias and higher morbidity and mortality (Figure 1).

On the other hand, the neurotropic capacity of SARS-CoV-2 is well known, as well as its ability to infect the nervous system and generate different central and peripheral manifestations, such as neuropathies [3-5].

The four cases had very peculiar characteristics. Cases 2-4 presented bilateral dysfunction of the PNs, which improved with combined rehabilitation therapy (electrostimulation, external negative pressure, incentive spirometer, etc.).

Farr et al. reported a cohort of 21 COVID-19 patients who manifested diaphragmatic dysfunction after IV, and in the post-extubation period manifested post-ventilator diaphragm dysfunction, post-intensive care syndrome, and critical illness myopathy; as well as muscle membrane dysfunction, microcirculatory changes associated with inflammation, and impaired glucose transporter type 4 translocation to the muscle membranes [10].

Borroni et al.reported two cases where DM was not accompanied by evidence of structural damage of the central nervous system through EEG use, where abnormalities were reported without determining that it was cortical myoclonus [7]. In Case 4 of the current report, no abnormal activity was documented in the EEG study, and cortical origin was ruled out, which, as reported in the literature, cannot rule out a causal association with COVID-19.

It is worth mentioning that we only describe four patients; therefore, it is difficult to make a generalization. This opens the doors to a more in-depth prospective study with a larger number of patients.

Another limitation of our study is the absence of diaphragmatic ultrasound studies that help us determine parameters such as diaphragmatic excursion time and percentage of diaphragmatic thickening, which in turn would have allowed us to determine treatment decisions (intubation or early tracheostomy) as well as functional prognosis of our patients. Finally, the information that arises from neurological complications due to COVID-19 is extensive and in the future, we will be able to consolidate the information necessary for decision-making.


In the cases in this report, the temporal sequence suggests but does not prove, that SARS-CoV-2 was a causal factor of PN neuropathy and DM, enriching the knowledge we have about the neurological manifestations of COVID-19. This case series improves the understanding of the sequelae of diaphragmatic paralysis and analyzes whether they are associated with acute infection, since the increased oxygen requirement occurred around eight days after hospital admission.

Vaccination has improved morbidity and mortality by decreasing the viral load in patients who have contracted the infection, so considering this type of neurological manifestations in T2DM patients, with an incomplete vaccination schedule or with more than nine months since the last booster, are factors to consider.

Finally, promoting multidisciplinary work in the approach to these types of cases and incorporating therapeutic interventions with respiratory physiotherapy and targeted rehabilitation, can offer patients a better prognosis.


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