Review of Respiratory Medicine - Volumen 23, Número 4 - December 2023

Case Reports

Heterotopic Ossification in COVID-19: An Association Not Yet Documented? Two-case report

Osificación heterotópica en COVID-19, ¿la asociación aún no documentada? Reporte de dos casos

ABSTRACT

Heterotopic ossification (OH) is defined as the formation of bone tissue in areas of soft tissue where there is usually no bone. It is a rare/underdiagnosed pathology usually related to paralysis and immobilization during the critical course of trauma, neurological lesions, acute respiratory distress syndrome (ARDS), surgery, or major burns. In the course of the SARS-CoV2 (new COVID-19) pandemic, cases of critically ill patients with OH were reported, interpreting that the magnitude of the inflammatory reaction, possible effect of the virus itself, and long periods of immobilization while the critical stage was taking place could be the determinants of this clinical entity.

During the hospitalization period of the cases that we will describe below, the occupational percentage was 166 % and 200 % and the workload of the nursing staff, measured by TISS-28, was 72 points, exceeding almost twice the possibilities labor. At the same time, motor rehabilitation by the Physiotherapy team was postponed due to the need to address urgent circumstances such as optimization of ventilatory support and participation in decubitus change maneuvers. In this way, we interpret that the great work overload that occurred during the pandemic conditioned an inadequate provision of early mobilization, resulting in a higher prevalence of OH in severe post-COVID patients when compared with ARDS due to other causes.

We present two cases of HO in patients who underwent ARDS due to SARS-CoV2 at times of high workload.

Case 1: A 48-year-old man, who was admitted to the ICU due to severe Pneumonia (NAC) due to COVID-19. History of obesity. He required 31 days of Mechanical Ventilation Assistance (AVM), 4 cycles of prone position (192 total hours), tracheostomy (TQT) on day 18, 23 days of neuromuscular blockers and 24 of sedation. Active-assisted mobilization begins on day 24 with a Medical Research Council (MRC) score of 38/60. A total of 52 days of hospitalization. Six months after discharge, bilateral HO of the hip was diagnosed.

Case 2: 58-year-old patient, admitted to the ICU with severe NAC due to COVID-19. History of Hypertension and Obesity. She required 39 days of AVM, two cycles of prone position (60 total hours), TQT on day 7. A total of 45 days in the ICU and 111 in the hospital. A year after discharge, bilateral OH of the hip was diagnosed.

Key words: COVID-19, Ossification, Heterotopic

RESUMEN

Se define como osificación heterotópica a la formación de tejido óseo en zonas de tejido blando en donde habitualmente no hay hueso. Se trata de una patología rara/ subdiagnosticada habitualmente relacionada con parálisis e inmovilización durante el curso crítico de traumatismos, lesiones neurológicas, síndrome de dificultad respiratoria aguda, cirugías o grandes quemados. En el transcurso de la pandemia por SARS-CoV-2 (nuevo COVID-19), se reportaron casos de pacientes críticos con osificación heterotópica y se interpretó que la magnitud de la reacción inflamatoria, posible efecto propio del virus, y los largos períodos de inmovilización mientras transcurría la etapa crítica podrían ser los determinantes de esta entidad clínica.

Durante el período de internación de los casos que describiremos a continuación, el porcentaje ocupacional fue del 166 % y del 200 % y la carga laboral del personal de enfermería, medida por TISS-28, fue de 72 puntos, lo que excedió casi al doble de las posibilidades laborales. Al mismo tiempo, la rehabilitación motora, por parte del equipo de kinesiología, se vio postergada ante la necesidad de atender circunstancias urgentes como la optimización del soporte ventilatorio y la participación en maniobras de cambios de decúbito. De este modo, interpretamos que la gran sobrecarga laboral acontecida durante la pandemia condicionó una inadecuada provisión de movilización temprana que dio como resultado una mayor prevalencia de osificación heterotópica en pacientes pos-COVID grave cuando se la compara con síndrome de dificultad respiratoria aguda por otras causas.

Presentamos dos casos de osificación heterotópica en pacientes que cursaron síndrome de dificultad respiratoria aguda por SARS-CoV-2 en momentos de alta carga laboral.

Caso 1: Paciente masculino de 48 años, que ingresó a la UCI por NAC grave por COVID-19. Antecedentes de obesidad. Requirió 31 días de AVM, 4 ciclos de posición prona (192 h total), TQT al día 18, 23 días de bloqueantes neuromusculares y 24 de sedación. Comienza la movilización activa-asistida al día 24 con MRC 38/60. Un total de 52 días de internación. A los 6 meses del alta, se diagnosticó osificación heterotópica bilateral de cadera.

Caso 2: Paciente de 58 años, que ingresa a UCI por NAC grave por COVID-19. Antecedentes de HTA y obesidad. Requirió 39 días de AVM, dos ciclos de posición prona (60 h total), TQT al día 7. Un total de 45 días de UCI y 111 de hospital. Al año del alta, se diagnostica osificación heterotópica bilateral de cadera.

Palabras clave: COVID-19, Osificación Heterópica

Received: 02/01/2023

Accepted : 07/25/2023

INTRODUCTION

The SARS-CoV 2 pandemic challenged the major­ity of the healthcare systems worldwide, with a high utilization rate of critical care and not enough qualified human resources. This situation gener­ated the need to meet the demand by employing personnel without the necessary expertise or by increasing the workload of the staff in those areas. In this context, new publications emerge daily on the stress experienced by the healthcare system and personnel.¹

Patients who suffered from severe COVID-19 experienced prolonged stays in the ICU, prolonged use of analgosedative and neuromuscular blocking agents, the need for mechanical ventilatory assis­tance (MVA), and extended prone positioning cycles. The simultaneous large number of critical patients exceeded the capacity of the personnel to provide adequate care, and this caused potential complica­tions related to the stress of healthcare workers.^1,2

Heterotopic ossification (HO) consists in the formation of bone tissue in areas of extraskeletal soft tissue where there is usually no bone.³

There are two typical presentations of HO: he­reditary and acquired. The latter is more prevalent and is primarily observed in patients with pro­longed immobilization following musculoskeletal traumatic injuries, neurological injuries, major burns, ARDS, or major surgeries.⁴

Prolonged immobilization is a common factor among patients with traumatic brain injury, spinal cord injury, ARDS from other causes, and severe COVID-19.⁵

Tissue injury results in the invasion of inflam­matory cells, causing an alteration in cells with mesenchymal origin. This impairment can lead to an osteogenic or osteochondrogenic program as mesenchymal cells differentiate into osteoblasts.⁶ The systemic inflammation, altered calcium me­tabolism, and local myositis seen in patients with COVID-19 could potentially trigger this effect.⁷

Recently, HO has been reported as a complica­tion associated with severe COVID-19 patients who underwent extended periods of MVA and prolonged hospital stay.⁷ In the vast majority of cases, heterotopic ossification was identified after hospital discharge, with pain, limited range of motion, and joint stiffness as the symptoms that triggered suspicion. Subsequently, the diagnosis was confirmed through imaging studies.^5,8,9

CASE REPORT 1

A 43-year-old male patient was admitted to the ICU for severe COVID-19 pneumonia, after two days of hospitalization in a general ward, where hypoxemia persisted despite receiving high concen­trations of oxygen. The only comorbidity presented by the patient was Class I obesity. Upon admission to the ICU, the patient required MVA and met the criteria for severe ARDS.

During the initial 10 days in the ICU, the patient underwent four alternating prolonged prone po­sitioning cycles, totaling 192 hours in that period and in that position. Until day 23 in the ICU, the patient received deep sedation and neuromuscular blocking agents. Complications included infectious events, a sacral pressure ulcer, and intensive care unit-acquired weakness (ICUAW). After discon­tinuing neuromuscular blockade and maintaining a superficial level of sedation, the patient’s muscle strength, assessed using the MRC scale, scored 38/60. This score fell below the cutoff point of 48/60. [10]. The patient was weaned from MVA on day 31 of ICU stay, and was discharged from the hospital on day 52 since admission, without requir­ing supplementary oxygen and with a MRC score of 50/60. Throughout the hospital stay, the individual had an average daily intake of 1044 mg of calcium, 728.6 mg of phosphorus, and 737.6 IU of vitamin D. The average daily intake of corticosteroids was 9.29 mg (0.093 mg/kg/day) of dexamethasone.

Six months after discharge, the patient pre­sented with pain and limited external rotation movement, and inability to abduct both hips. A pelvic and hip CT scan was requested, revealing bilateral HO of the hip (Fig. 1A and 1B).

CASE REPORT 2

A 58-year-old patient, hypertensive and with Class 1 obesity, hospitalized in a general ward and diag­nosed with severe COVID-19 pneumonia suffered an ischemic stroke and was transferred to the ICU. The patient’s respiratory condition deteriorated, requiring MVA. The patient received two prone positioning cycles, totaling 60 hours within the first 10 days of ICU stay. He/she experienced infectious complications and a sacral pressure ulcer. Weaning from MVA was achieved after 39 days. The patient remained in the ICU for a total of 45 days and was discharged from the hospital 111 days since initial admission. Throughout the hospital stay, he/she had an average daily intake of 2,359.34 mg of calcium, 1,538.6 mg of phosphorus, and 1,190.8 IU of vitamin D. The average daily intake of corticosteroids was 7.75 mg (0.072 mg/ kg/day) of dexamethasone. Upon discharge, the pa­tient did not require oxygen therapy but presented with a moderate right brachio-crural motor deficit, ataxia, visual field impairment, and gastrostomy tube feeding due to swallowing disorder. One year post-discharge, there was functional improve­ment, but with evident limitations in movement unrelated to the motor deficit. A pelvic CT scan was performed, revealing heterotopic ossification in both hips. (Fig 2A and 2B).

 

As of the current date, there has been no surgi­cal opportunity.

DISCUSSION

The published cases of HO in patients with COV­ID-19 occurred in the context of severe forms of the disease, involving prolonged hospitalizations and invasive ventilatory support due to ARDS^5-9,11-13. As with any cause of severe ARDS, paralysis and deep sedation were part of the therapeutic approach.^14,15

During the stay of the two described patients, the occupancy rate of the ICU exceeded between 66 % and 100% its maximum capacity. That is to say, the occupational rate was 16 6% and 200 %, and the workload of the nursing staff, measured by TISS-28, was 72 points, nearly double the workload manageable by a nurse [own data]. Infectious complications such as mechanical ventilation-associated pneumonia, catheter-asso­ciated infections, and pressure ulcers caused by the decubitus position tripled the average value of the service. In this context, motor kinesiotherapy was postponed due to the need to address urgent circumstances, contributing to prolonged periods of immobilization. The reduced bedside times interfered with the proper implementation of ventilatory weaning protocols, resulting in longer periods of MVA and ICU stay. Consequently, there was greater use of neuromuscular blocking agents and sedatives, generating prolonged patient im­mobilization.

Some publications addressing the pathogenesis of HO consider immobilization as an associated factor, without specifying the differences between active and passive motion. The work of Stoira et al, shows a four times higher prevalence in COVID-19 distressed patients compared to those with other causes of ARDS.

We do not know the dose values of parathyroid hormone, phosphorus, or vitamin D. However, the intake of calcium, vitamin D, and phosphorus were adequate for baseline needs. Regarding the use of corticosteroids, the doses were very high, and were consistent with what was reported by Stoira et al. While some characteristics specific to SARS-CoV-2 infection are suggested, such as humoral alterations, disturbances in calcium metabolism, inflammatory response, and direct muscle injury, the conclusion is that prolonged immobilization is the only relevant factor in the multivariate analy­sis. The recommendation is early passive motion as a preventive method for the development of HO.⁷

CONCLUSION

Our case report identifies factors that have been mentioned in the literature as possible causes of HO in COVID-19 patients. This includes the prolonged use of sedatives and neuromuscular blockers in patients experiencing intense inflammation. The critical condition and therapeutic strategy result in long periods of immobilization during the ICU stay.

However, the above description does not fully explain the higher prevalence of HO in patients who experienced ARDS due to COVID-19 when compared to patients who suffered ARDS from other causes. Thus, there are no differences regarding the inflam­matory processes or the recommendation to use deep analgosedation and neuromuscular blockade.

We interpret that the workload generated by patient care during the pandemic peaks had a sig­nificant influence and caused unusual situations in daily practice. This included prioritizing respi­ratory kinesiotherapy over motor intervention, difficulty in implementing MVA weaning protocols, and less time spent at the patient’s bedside due to isolation conditions.

As a result, this could have led to more days of sedatives and neuromuscular blocking agents, prolonged mechanical ventilation, and the delay or impossibility of passive and active motion in patients (all circumstances favoring heterotopic ossification).

We believe that the higher prevalence of HO in severe COVID-19 could serve as a stress marker of the healthcare system. We think it is relevant to conduct future research to assess this association.

Conflict of interest

Authors have no conflicts of interest to declare.

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