key: cord-285944-8lapwnuw
authors: Suwanwongse, Kulachanya; Shabarek, Nehad
title: Hyperpyrexia in COVID‐19 patients
date: 2020-06-10
journal: J Med Virol
DOI: 10.1002/jmv.26154
sha: 
doc_id: 285944
cord_uid: 8lapwnuw

Coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a global health emergency, in which its effective treatment and prevention remain obscured. Hyperpyrexia is an elevation of body temperature (BT) above 106.7 °F (41.5 °C) due to an abnormally increased hypothalamic thermo‐regulatory set. The pathophysiology, impact, and outcomes of hyperpyrexia in COVID‐19 patients have not yet been studied. Herein, we present clinical features and outcomes of six COVID‐19 patients who had developed hyperpyrexia during hospitalization. All patients expired shortly after the onset of hyperpyrexia. Hyperpyrexia seems to adversely impact the outcomes and mortality in patients with COVID‐19. The underlying mechanisms of developing hyperpyrexia in COVID‐19 are mysterious. We propose it may be caused by SARS‐CoV‐2 related brain injury, exuberant immune response, and thrombus formation. More research is needed to verify our results. Understanding the association between hyperpyrexia and SARS‐CoV‐2 will help to elucidate the COVID‐19 pathogenesis, which is mandatory for developing effective treatment strategies. This article is protected by copyright. All rights reserved.

Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has shaken the global health systems, with more than five million people, have infected and of which almost 400,000 died [1] . The clinical courses of COVID-19 vary from asymptomatic to multi-organ failure and death [2] . Despite the immense effort on COVID-19 research, the mechanisms underlying the progression to severe disease remain mysterious. Several clinical factors, including certain co-morbidities, hypoxia, elevated inflammatory markers, and acute kidney injury, are identified as the ominous clinical predictors of SARS-CoV-2 infection [2] [3] [4] .

Hyperpyrexia is defined as an elevation of body temperature (BT) above 106.7 °F (41.5 °C) to achieve an abnormally increased hypothalamic thermo-regulatory threshold, as opposed to hyperthermia, which is an elevation of core BT exceeding the normal hypothalamic thermo-regulatory limit [5, 6] . The most common cause of hyperpyrexia is brain dysfunction, while infection and sepsis are thought to be infrequent causes [6, 7] . The effect of hyperpyrexia on patients who have infectious diseases is contradictory. Hyperpyrexia may adversely impact survival in patients with bacterial infection, but may not increase mortality among patients with viral illnesses [7, 8] . To date, the impact of hyperpyrexia on the clinical course and prognoses of COVID-19 patients has not yet been reported. Herein, we are presenting the clinical features and outcomes of confirmed COVID-19 patients who had developed hyperpyrexia and were admitted to our COVID-19 unit between 1-10 April 2020.

Six patients were identified. Our patients' median age was 60.5 years (ranges, 54-62 years). Four were females, and two were males. Five patients had multiple comorbidities proven to negatively impact COVID-19 prognoses. Fever, dyspnea, and altered mental status were among the most prevalent clinical manifestations. Gastrointestinal symptoms were reported in one patient. The median duration of illness before hospitalization was two days (ranges, 1-7 days). COVID-19 was diagnoses by a positive SARS-CoV-2 RT-PCR test from nasopharyngeal swab specimens. All patients presented with hypoxia (oxygen saturation on room air ranges, 60-89%) and had abnormal chest x-ray (CXR) compatible with viral pneumonia (Figure 1 ). Two patients did not have lymphocytopenia initially but later developed during the hospital course. Ferritin was measured in five patients, and all revealed the remarkably high result. C-reactive protein was initially elevated in four of five patients, and D-dimer was high in five of five patients.

All patients received a five-day course of hydroxychloroquine (400 mg twice daily on the first day, and 200 mg twice daily for the following four days) for the COVID-19 treatment per hospital protocol, and intravenous ceftriaxone and azithromycin to cover possible bacterial pneumonia. However, blood culture revealed negative results in all. None received steroids, immunosuppressive agents, or convalescent plasma.

All patients were intubated due to acute hypoxemic respiratory failure within three days of hospitalization, of which four were intubated during the first admission day. The positive end-expiratory pressure (PEEP) and the fraction of inspired oxygen (FiO2) requirement ranged from 8-20 cmH2O, and 40-100%, respectively. Five patients had developed acute kidney injury. Median onset of hyperpyrexia was eight days from admission (ranges, 6-12) with the measured axillary BT between 107.2 and 109.7 °F. External cooling with ice-pads was applied as well as oral acetaminophen administration to control the BT. Patients 4 and 5 showed improvement of lungs mechanics demonstrated by a decrease requirement of PEEP and FiO2 over the hospitalization courses However, both patients failed spontaneous breathing trials due to impair of consciousness, despite not receiving any sedation. All patients ultimately expired. The duration from the first occurrence of hyperpyrexia to death ranged between 3 to 45 hours (mean 17 hours, median 9.5 hours). Table 1 summarizes the demographic, clinical features, and outcomes of the included patients. Figure 2 demonstrates the dynamic changes of measured BT (°F) of each patient.

Extremely high measured core BT is a devastating condition requiring urgent management and prompt recognition of the causes. High fever leads to direct cellular damages and worsens inflammatory responses so the cooling methods should be implemented immediately [9] . In addition, the causes of severely elevated BT need to be determined as many etiologies can lead to death even the fever symptom is under control [6] . It is important to distinguish whether the high BT is a result of hyperpyrexia or hyperthermia as the etiologies underlying these two conditions are different. The pathology of hyperpyrexia is centrally targeted, resulting in a reset of hypothalamic regulation to a higher level, whereas hyperthermia is usually caused by peripheral etiologies leading to excessive heat production or defective heat loss [6] .

Our patients were deemed to have severely elevated BT from hyperpyrexia because of the high ranges of BT fluctuation and the elevation of inflammatory markers, especially C-reactive protein [10] . Besides, our patients did not have muscle rigidity nor developed rhabdomyolysis, which are the characteristic features in patients with hyperthermia [6] .

To date, no published literature describes the pathophysiology of hyperpyrexia in COVID-19. We propose three possible underlying mechanisms based on our current knowledge: 1) direct brain injury from SARS-CoV-2, 2) persistent immune dysfunction and dysregulation of cytokines, and 3) vascular thrombosis.

SARS-CoV-2 binds angiotensin-converting enzyme 2 (ACE2) receptors to gain cellular entry into human organs [11] . ACE2 receptors are highly expressed in airway epithelia, lung parenchyma, and gastrointestinal epithelia explaining why dyspnea, cough, and GI complaints are predominately symptoms in COVID-19 patients [12] . Recent evidence suggested that neuron, astrocytes, and oligodendrocytes also have ACE2 receptors expression in a specific spatial localization pattern [13] . The direct invasion of SARS-CoV-2 to the nervous systems may explain COVID-19 related neurological complications, including stroke, encephalitis, and encephalopathy.

Brain injury from the SARS-CoV-2 invasion may lead to hyperpyrexia by two distinct mechanisms: direct injury to the neurons in hypothalamic-thermoregulatory pathways and injury to other parts of the brain leading to the local production of proinflammatory and pyrogenic cytokines. Absence of normal circadian rhythm and the presence of hypothermia are pathognomonic signs of hyperpyrexia caused by brain injury [14] . According to our case series, the lack of normal daily temperature variation in patient 4 and 5, and the presence of hypothermia in patient 1 and 5 support the hypothesis that direct brain injury from SARS-CoV-2 leads to hyperpyrexia.

SARS-CoV-2 may cause injury to the brain-stem respiratory center explaining why COVID-19 patients often report lesser perception of dyspnea than the actual degree of hypoxia and the extent of lung pathology [15] . Patient 4 and 5 showed discrepancy between the improvement of COVID-19 pneumonia, demonstrated by a decrease in oxygen requirement and better pulmonary mechanics, compared with the degree of respiratory function compromise, illustrated by an absence of spontaneous breathing despite sedation vacation. This further supports the possibility of brain injury from SARS-CoV-2.

Moreover, our case series revealed a remarkably high incidence of altering mental status (66.7%) as a presenting complaint, which indicated that many had encephalopathy before the admission. The early onset of encephalopathy (median 2 days (ranges, 1-7 days)) raises the possibility that this encephalopathy was caused by the direct neuro-invasion of SARS-CoV-2 rather than its indirect effect from toxicmetabolic encephalopathy.

SARS-CoV-2 leads to a unique pattern of immune dysfunction characterized by a defective antigen presentation and lymphoid cells, but preserved monocytes function to secrete TNF-α and IL-6 [16] . Severe COVID-19 patients have substantially higher serum levels of pro-inflammatory cytokines (TNF-α, IL-1, and IL-6) and chemokines (IL-8) than individuals with mild disease [17] . IL-6 can also be used as a marker to predict SARS-CoV-2 disease deterioration [18] . IL-1, IL-6, and IL-8 are known endogenous pyrogens [19] . Studies compared the differential cytokines expression in malaria patients with and without hyperpyrexia discovered that IL-6 was significantly higher in the hyperpyrexia group [20] . Thus, high IL-6 may associate with hyperpyrexia in COVID-19 patients.

COVID-19 patients have an increased risk of arterial and venous thrombosis [21] . SARS-CoV-2 can directly destroy vascular endothelial cells and induce uncontrolled inflammatory responses leading to systemic thrombosis and generalized coagulopathy. Hematoma formation is well recognized but uncommon cause of hyperpyrexia [6] . Although this is the least likely possibility in our cases, it should be considered especially for patient 6, who had an 8-fold increase in D-dimer and a sudden increase in oxygen requirement during hospitalization. Furthermore, patient 6 is the only patient who had survived more than 24 hours after the onset of hyperpyrexia, which may suggest a different etiology underlying her extremely high BT.

Our case series revealed 100% mortality and suggested that hyperpyrexia is a poor prognostic outcome and may predict mortality in patients with COVID-19. However, this assumption urgently needs more evidence as our case series is limited to only six patients. Another interesting point is that the patients' age in our case series is restricted to their 50 to 60s. If this unique age group involvement is existed in larger studies, it will be worthwhile to investigate the reasons.

Our case series also highlights the need to determine underlying mechanisms of hyperpyrexia in COVID-19 patients as each cause requires different management. Anti-viral drugs, neuroprotective agents, and medications modifying neurotransmitters will be beneficial if the direct invasion of SARS-CoV-2 to the nervous systems is an underlying etiology. Immunosuppressive agents, particularly drugs targeting the causative cytokines, will be of greatest benefit if the immune dysregulation is identified. In contrast, thrombolytic treatment is mandatory if the patients have thromboembolic complications.

Our case series showed 100% mortality in COVID-19 patients who had developed hyperpyrexia. Hyperpyrexia may indicate poor clinical outcomes and worsen mortality in patients with COVID-19. The underlying mechanisms of hyperpyrexia in COVID-19 are unknown but may be a result of SARS-CoV-2 related brain injury, exuberant immune response, and thrombus formation. Figure 1 : CXR of each patient: 1 -bilateral peri-hilar predominant infiltrates 2bibasilar alveolar infiltrates 3 -bibasilar alveolar infiltrates, predominately on the leftsided 4-multifocal patchy pneumonic infiltration in the bilateral peripheral lung field 5-bilateral multifocal patchy pneumonic infiltration predominantly on the right 6patchy ground-glass infiltrates throughout the left lung and at the right lung base 

WHO Coronavirus disease 2019 (COVID-19) situation report -132

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