When an infected person expels virus-laden droplets and someone else inhales them, the novel coronavirus (Covid-19 or SARS-CoV-2) enters the nose and throat and finds a particularly welcome home in the lining of the nose. As the virus multiplies, an infected person may shed copious amounts of it, especially during the first week or so. Symptoms may be absent at this point. Alternatively, the virus’ new victim may develop a fever, dry cough, sore throat, loss of smell and taste, or head and body aches. If the immune system doesn’t beat back the virus during this initial phase, it then marches down the windpipe to attack the lungs, where it can turn deadly by invading the thinner, distant branches of the lung’s respiratory tree end — the tiny air sacs called alveoli.
Normally, oxygen crosses the alveoli into the capillaries that lie beside the air sacs; the oxygen is then carried to the rest of the body. But as the immune system fights with the invader, the battle itself disrupts this healthy oxygen transfer. Front-line white blood cells release inflammatory molecules called chemokines, which in turn summon more immune cells that target and kill virus-infected cells, leaving a stew of fluid and dead cells — pus — behind. This is the underlying pathology of pneumonia, with its corresponding symptoms: coughing, fever, and rapid, shallow respiration. Some Covid-19 patients recover, sometimes with no more support than oxygen breathed in through nasal prongs. But others deteriorate, often quite suddenly, developing a condition called acute respiratory distress syndrome (ARDS). Oxygen levels in their blood plummet and they struggle ever harder to breathe, but their lungs may be damaged beyond repair, such that ventilators cannot heal them.
Some clinicians suspect that the driving force in many gravely ill patients’ downhill trajectories is a disastrous overreaction of the immune system known as a “cytokine storm,” which other viral infections are known to trigger. Cytokines are chemical signaling molecules that guide a healthy immune response; but in a cytokine storm, levels of certain cytokines soar far beyond what’s needed, and immune cells start to attack healthy tissues. Blood vessels leak, blood pressure drops, clots form, and catastrophic organ failure can ensue.
In patients with SCLS, such cytokine storms are thought to trigger capillary leaks, and thus chances are that an SCLS patient with Covid-19, possibly on an otherwise successful therapy of IVIG, will have their course of hospitalization greatly complicated by an episode of SCLS.
We now have the first reported case of an SCLS patient in Paris who had a mild version of Covid-19, and yet the virus triggered an episode of SCLS that led to organ damage and death. The report is reprinted below and is otherwise available from https://www.amjmed.com/article/S0002-9343(20)30373-9/pdf As you will read, the 45-year-old female had been episode-free for 7 years, and her dosage of IVIG had been tapered down from the recommended high dose of 2 gr/kg/month to as little as 0.5 gr/kg/month. Therefore, the French doctors, who are very knowledgeable about SCLS — they were the first to experiment with IVIG as prevention for SCLS in the late 1990s and early 2000s — conclude that "the immunoglobulin treatment in our patient might have been insufficient to prevent such a virulent virus, ... [and thus] an intensified IVIG treatment using increased dosages in all Clarkson’s disease patients (2g/kg monthly) should be considered" during this pandemic.
Some physicians have tried to calm the severe cytokine storms on Covid-19 patients who do not have SCLS by giving them IVIG, and there is a recent article out of Italy that advocates trying IVIG on gravely ill patients who do not respond to other treatments, see https://www.sciencedirect.com/science/article/abs/pii/S156899722030121X (If you wish to read this article, contact me and I will send it to you.)
To date, there has been only one report out of China of the successful administration of IVIG in three non-SCLS patients with severe Covid-19, but randomized clinical trials have been started in that country, see https://academic.oup.com/ofid/article-pdf/7/3/ofaa102/32987821/ofaa102.pdf Since several months will pass before these ongoing trials are concluded, the Italian physicians argue that IVIG already meets all the criteria for off-label use in severe Covid-19 infections, in view of their immunomodulatory and protective action against superinfections and their cytokine storms.
So what should SCLS patients do in anticipation of becoming infected with Covid-19 sooner or later, once we relax our current state of isolation? Here are my recommendations:
1) If you are not already on a high dose of 2 gr/kg/month, speak with your physician(s) about increasing your dose until there is a vaccine against Covid-19. "An ounce of prevention is worth a pound of cure."
2) Even if you are already on a high dose of 2 gr/kg/month, try to reach an understanding with your physician(s) about getting an immediate extra dose of IVIG if you develop symptoms of Covid-19 or if you test positive for Covid-19. "An ounce of prevention is worth a pound of cure."
Here is the article you should take to heart and share with your physician(s):
SARS-CoV-2 Induces Acute and Refractory Relapse of Systemic Capillary Leak Syndrome (Clarkson’s disease)
To appear in finalized form in The American Journal of Medicine, https://doi.org/10.1016/j.amjmed.2020.03.057
Marc Pineton de Chambrun MD, MSc, Fleur Cohen-Aubart MD, PhD, Dirk W. Donker MD, PhD, Pierre-Louis Cariou MD, Charles-Edouard Luyt MD, PhD, Alain Combes MD, PhD, Zahir Amoura MD, MSc
Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital de la Pitié- Salpêtrière, Service de Médecine Interne 2, Maladies Auto-Immunes Et Systémiques Rares, 75013-Paris, France
The systemic capillary-leak syndrome (SCLS), also known as Clarkson’s disease, is a rare condition characterized by recurrent episodes of capillary hyperpermeability in the context of a monoclonal gammopathy. We have previously shown that prophylactic treatment with intravenous immunoglobulins (IVIG) significantly reduces relapse and improve survival. SCLS episodes are thought to have an infectious trigger, especially mediated by viruses and a flu-like viral syndrome was reported in more than half of the episodes in a large cohort of Clarkson’s disease flares.
A 45-year-old woman, with a 7-year history of IgG Kappa monoclonal gammopathy-associated SCLS, was recently admitted to our hospital for a planned immunoglobulin infusion. She regularly received IVIG since her diagnosis of Clarkson’s disease at an initial dosage of 2g/kg, with progressive tapering to 0.5g/kg of body weight monthly. This preventive treatment protected her from having any relapse.
When she was admitted in March 2020, she complained about nausea and vomiting and a 10 kg increase of body weight. She had no fever or any respiratory symptoms, but hypotension (80/40 mmHg) with elevated heart rate (110 bpm). Laboratory findings were typical for an acute episode (hemoglobin 19.1 g/dL, proteinemia: 42g/L). Evolution was unfavorable with severe hypovolemic shock, multiple organ failure and 4-limb compartment syndrome cumulating into refractory cardiac arrest. SARS-CoV-2 PCR turned out to be positive as sampled by tracheal aspiration.
The pathophysiology of SCLS is unknown. Whether the monoclonal component contributes to the pathogenesis of the disease and the mode of action of IVIG remains elusive. Still, the role of viruses as a trigger for acute relapses of the disease has repeatedly been described, as holds particularly for the influenza virus. SARS-CoV-2, a novel coronavirus that spread in early 2020 from the region of Wuhan in China, is characterized mainly by a severe acute respiratory distress syndrome. In this patient, the viral infection, although poorly symptomatic, can be considered as the trigger of the relapse.
We believe that this report contributes to our mechanistic understanding of several urgent considerations. Firstly, our patient died from a severe episode triggered by a SARS-CoV-2 infection without demonstrating neither any signs of severe SARS-CoV-2 infection.
Secondly, she did not experience any acute relapse during the previous 7 years while under preventive treatment with IVIG, yet she died after being infected with this new pandemic virus. Obviously, IVIG preparations contain virus-specific immunoglobulins that may protect patients with Clarkson’s disease against seasonal viral infections. Yet, in the setting of this new pandemic virus, the protection generally granted by IVIG may vanish because of the lack of SARS-CoV-2 specific immunoglobulins in available preparations.
Thirdly, an additional aspect of the immunoglobulin treatment in our patient might have been insufficient to prevent such a virulent virus, i.e. the individual dosage. Therefore, an intensified IVIG treatment using increased dosages in all Clarkson’s disease patients (2g/kg monthly) should be considered at least during the beginning of the pandemic.
Lastly, SCLS patients should be considered at very high risk for an acute relapse while facing this new coronavirus and maximal isolation should imperatively be advocated.