Covid-19 and leptospirosis: Cytokine storm and the use of steroids

Covid-19, caused by the corona virus SARS CoV-2, is still ravaging the world in its global run. It seems that a majority of those affected (maybe 81%) are asymptomatic or have only mild respiratory disease; severe disease occurs in c. 14% and c. 5% develop critical disease. ¹ The majority of these ² develop acute respiratory distress syndrome (ARDS) and/or multiple-organ failure occur rapidly, with rapid fatality. The reported incidence of ARDS is around 15.6–31% ³ whose mortality may reach 50%.^4,5

Cytokine storm is considered to be the main incriminating factor. ⁶ This deregulated cytokine and chemokine response is the most important step in the pathogenesis of serious Covid-19. Therefore, tackling it is vital in the management of this disease.

Leptospirosis is a potentially fatal zoonotic disease endemic to many tropical areas. It is caused by exposure to pathogenic leptospira shed in the urine of host animals, especially rats. ⁷ While mice are resistant to fatal infection and serve as natural reservoirs, humans are accidental hosts but may face potentially fatal outcome. As with Covid-19, most human leptospiral infections are mild or asymptomatic. ⁷ Some 5–15% of patients develop Weil’s disease,^8–10 where pulmonary involvement is prominent (20–70%), ¹¹ but clinical manifestations may range from mild cough to severe haemoptysis and ARDS. Symptoms usually appear between the fourth and sixth day of illness, and the disease may evolve very rapidly with fatality before 72 h. ¹² In those who develop ARDS, the mortality rate may be > 50%. ¹³

With high leptospiraemia innate immune mechanisms trigger a cytokine storm with elevated levels of IL-6, TNF-α and a number of other cytokines,^14–16 which may be associated with disease severity. ¹⁷ Pro-inflammatory cytokines and chemokines released in huge quantities attract many inflammatory cells, resulting in their excessive infiltration into various tissues especially the lung causing injury and ultimately multiple-organ failure. ⁶ Deregulated cytokine production may result in a state of immunoparalysis, associated organ failure and ultimately death. This cytokine storm may also be precipitated by the initiation of chemotherapy and is clinically characterised by an acute febrile inflammatory reaction known as the Jarisch–Herxheimer reaction, ¹⁸ originally described with mercury treatment in treatment of syphilis.^19,20 Higher interleukin levels are known to be associated with pulmonary involvement and fatality.^14,21

High dose steroids have long been used to ameliorate the effects of cytokine storm in leptospirosis with an observed benefit in survival. ²² However, no well-designed randomised clinical trial to generate robust evidence has ever been attempted. ²³ Nevertheless, data accumulated over the years have led several national guidelines^24,25 to recommend the use of high dose steroids in early ARDS in leptospirosis.

Covid-19 and leptospirosis are two quite different infections but have many similarities. Both have almost the same incubation period; the majority of victims remain asymptomatic or have very mild symptoms; the pattern of respiratory involvement is very similar with ARDS being its most deleterious outcome, and the mortality rate is almost the same.

A cytokine storm has been incriminated as the main precipitating factor in both diseases. Steroids have been used in the treatment of ARDS in leptospirosis even though scientifically robust evidence is lacking. It is unlikely that a strictly designed trial is likely in the near future. The RECOVERY trial ²⁶ supports the use of steroids in ARDS due to Covid-19. However, gaps remain in the final verdict. ²⁷ And akin to leptospirosis, it is plausible that we may never see an adequately powered randomised trial. Absence of ‘evidence’ cannot be considered as evidence of ‘absence’. Given the commonality of cytokine storm in the pathophysiology of ARDS in both Covid-19 and leptospirosis and the proven benefit of steroids to alter the clinical course of ARDS for the better in leptospirosis, it is conceivable that the same mechanism may hold true in Covid-19.

There are other treatments that require verification, especially as since the start of the Covid-19 pandemic, several experimental drugs with unknown efficacy and potential adverse effects have been utilised in certain circles. An interesting treatment option is low dose radiation therapy for ARDS,^28,29 but as in the case of ARDS, due to leptospirosis, quality studies are wanting; there are no known reports of radiation therapy being tried in leptospirosis.

SARS CoV-2 and leptospira, one a virus and the other a bacterium, are two species separated by millions of years of evolution, yet produce illnesses with startling similarity. Hopefully, more light will soon be shed on features analogous to both infections.