H5N1

Cytokine levels in critically ill patients with COVID-19 and other conditions

Via JAMA Network: Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions.

An abnormally strong proinflammatory response known as “cytokine storm” may play an important role in the pathophysiology of coronavirus disease 2019 (COVID-19), although cytokine storm remains ill defined. Sinha and colleagues reported that although IL-6 levels are elevated in severe COVID-19, they are lower than levels usually observed in (non–COVID-19) acute respiratory distress syndrome (ARDS). However, this comparison is limited by the use of different assays, which are not well standardized. We compared cytokine levels in critically ill patients with COVID-19 vs levels in patients with other critical illnesses.  

Methods 

All patients in this study were admitted to the intensive care unit (ICU) of Radboud University Medical Center. Plasma concentrations of the proinflammatory cytokines tumor necrosis factor (TNF), IL-6, and IL-8 were determined in consecutive mechanically ventilated patients with COVID-19 with ARDS (partial pressure of oxygen/fraction of inspired oxygen ratio <300; sampled within 48 hours after ICU admission), bacterial septic shock with or without ARDS (sampled within 24 hours after septic shock diagnosis), out-of-hospital cardiac arrest (OHCA; sampled within 24 hours after ICU admission), and multiple traumas (sampled within 24 hours after trauma). 

The patients with sepsis and trauma are part of larger published cohorts, whereas data of 14 patients with OHCA were previously published. Sampling occurred between 2010 and 2020 (Table). Patients with immunological insufficiencies were excluded, defined as chronic/concomitant use of immunosuppressive medication, chemotherapy/radiotherapy in the last year or in the past for (non-)Hodgkin lymphoma, or humoral/cellular deficiencies. 

Cytokines in all cohorts were determined using the same methodology (Milliplex assay, Millipore, on a MAGPIX instrument, Luminex Corporation) by the same technician using the same protocol. Patient characteristics were analyzed using Fisher exact or Kruskal-Wallis tests followed by Dunn post hoc tests. Cytokine data are presented as geometric means (95% CIs) and analyzed using 1-way analysis of variance on log-transformed data followed by Dunnett post hoc tests. 

Data were analyzed using Graphpad Prism version 8.3.0 (Graphpad Software). A 2-sided P < .05 was considered statistically significant. The study was carried out in accordance with the applicable rules concerning the review of research ethics committees and informed consent in the Netherlands. All patients or legal representatives were informed about the study details and allowed to abstain from participation. Patients who consented to participate or their next of kin provided oral consent.  

Results 

There were 46 patients with COVID-19 with ARDS, 51 with septic shock with ARDS, 15 with septic shock without ARDS, 30 with OHCA, and 62 with multiple traumas. There were no significant differences in sex or age between patients with COVID-19 and other patient groups (Table). Patients with COVID-19 had a higher body mass index and prevalence of diabetes than patients with OHCA and trauma. In COVID-19, cardiovascular insufficiency was more common, overall disease severity and leukocyte counts were lower, and lung injury was more severe compared with the other groups. 

Levels of all 3 cytokines were significantly lower in patients with COVID-19 than in patients with septic shock with ARDS; the geometric means were 22 pg/mL (95% CI, 18-27) vs 40 pg/mL (95% CI, 30-55) (P < .01) for TNF; 48 pg/mL (95% CI, 35-66) vs 376 pg/mL (95% CI, 190-744) (P < .001) for IL-6; and 27 pg/mL (95% CI, 23-33) vs 215 pg/mL (95% CI, 133-347) (P < .001) for IL-8 (depicted in the Figure on a log scale). Patients with COVID-19 also displayed significantly lower IL-6 and IL-8 concentrations compared with patients with septic shock without ARDS (Figure). TNF levels in patients with COVID-19 were higher than those in trauma patients, whereas no differences between patients with COVID-19 and OHCA or trauma were present for IL-6. For IL-8, lower concentrations were found in patients with COVID-19 compared with patients with OHCA, while no differences vs the trauma group were observed.  

Discussion 

In this study, critically ill patients with COVID-19 with ARDS had circulating cytokine levels that were lower compared with patients with bacterial sepsis and similar to other critically ill patients. These findings are in line with lower leukocyte counts observed in patients with COVID-19, and are possibly due to lower overall disease severity, despite the presence of severe pulmonary injury. 

The findings of this preliminary analysis suggest COVID-19 may not be characterized by cytokine storm. Whether anticytokine therapies will benefit patients with COVID-19 remains to be determined. Limitations of the study include the small sample sizes, single center involved, and the use of different lots of the same assays without data on lot-to-lot variability.

Hyperinflammatory shock in children during COVID-19 pandemic

Via The Lancet: Hyperinflammatory shock in children during COVID-19 pandemic. Excerpt:

South Thames Retrieval Service in London, UK, provides paediatric intensive care support and retrieval to 2 million children in South East England. During a period of 10 days in mid-April, 2020, we noted an unprecedented cluster of eight children with hyperinflammatory shock, showing features similar to atypical Kawasaki disease, Kawasaki disease shock syndrome, or toxic shock syndrome (typical number is one or two children per week). This case cluster formed the basis of a national alert. 

All children were previously fit and well. Six of the children were of Afro-Caribbean descent, and five of the children were boys. All children except one were well above the 75th centile for weight. Four children had known family exposure to coronavirus disease 2019 (COVID-19). Demographics, clinical findings, imaging findings, treatment, and outcome for this cluster of eight children are shown in the table.

Clinical presentations were similar, with unrelenting fever (38–40°C), variable rash, conjunctivitis, peripheral oedema, and generalised extremity pain with significant gastrointestinal symptoms. All progressed to warm, vasoplegic shock, refractory to volume resuscitation and eventually requiring noradrenaline and milrinone for haemodynamic support. Most of the children had no significant respiratory involvement, although seven of the children required mechanical ventilation for cardiovascular stabilisation. Other notable features (besides persistent fever and rash) included development of small pleural, pericardial, and ascitic effusions, suggestive of a diffuse inflammatory process.

All children tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on broncho-alveolar lavage or nasopharyngeal aspirates. Despite being critically unwell, with laboratory evidence of infection or inflammation3 including elevated concentrations of C-reactive protein, procalcitonin, ferritin, triglycerides, and D-dimers, no pathological organism was identified in seven of the children. Adenovirus and enterovirus were isolated in one child.

Baseline electrocardiograms were non-specific; however, a common echocardiographic finding was echo-bright coronary vessels (appendix), which progressed to giant coronary aneurysm in one patient within a week of discharge from paediatric intensive care (appendix). One child developed arrhythmia with refractory shock, requiring extracorporeal life support, and died from a large cerebrovascular infarct. The myocardial involvement2 in this syndrome is evidenced by very elevated cardiac enzymes during the course of illness.

All children were given intravenous immunoglobulin (2 g/kg) in the first 24 h, and antibiotic cover including ceftriaxone and clindamycin. Subsequently, six children have been given 50 mg/kg aspirin. All of the children were discharged from PICU after 4–6 days. Since discharge, two of the children have tested positive for SARS-CoV-2 (including the child who died, in whom SARS-CoV-2 was detected post mortem). All children are receiving ongoing surveillance for coronary abnormalities.

We suggest that this clinical picture represents a new phenomenon affecting previously asymptomatic children with SARS-CoV-2 infection manifesting as a hyperinflammatory syndrome with multiorgan involvement similar to Kawasaki disease shock syndrome. The multifaceted nature of the disease course underlines the need for multispecialty input (intensive care, cardiology, infectious diseases, immunology, and rheumatology).

The intention of this Correspondence is to bring this subset of children to the attention of the wider paediatric community and to optimise early recognition and management. As this Correspondence goes to press, 1 week after the initial submission, the Evelina London Children's Hospital paediatric intensive care unit has managed more than 20 children with similar clinical presentation, the first ten of whom tested positive for antibody (including the original eight children in the cohort described above).

Picard: Streptococcus outbreak in Canada is part of a larger story

Via The Globe and Mail, André Picard writes: Streptococcus outbreak in Canada is part of a larger story. You'd better read the whole article, and take notes. Excerpt:

The Middlesex-London Health Unit has issued an alert about a continuing outbreak of invasive group A streptococcus (iGAS). 

There have been 132 reported cases of the bacterial infection since April, 2016. 

To date, there have been nine deaths, 20 cases of necrotizing fasciitis (flesh-eating disease), 20 cases of toxic shock and 29 others have ended up in intensive care with other grave symptoms.  

Those numbers are frightening, but they are just a small part of a much larger story.  

In recent months, there have been similar outbreaks of this particularly nasty strain of strep A in Toronto, Montreal, Vancouver, Calgary and likely elsewhere.  

In every city, there have been deaths and a number of amputations caused by flesh-eating disease, but the story has stayed under the radar because this type of infection largely affects intravenous-drug users and the precariously-housed, especially those living in shelters. 

Disease and death stalk marginalized communities quite routinely, so outbreaks of infectious diseases like iGAS don't generate much attention from public-health officials and the media. That is true in London as much as anywhere else. 

But what happened in London is that strep A started harming people in the general population as well.  

"There has also been an increase in iGAS infections among people who have no connection, and are not related, to the outbreak in people who inject drugs or who are under-housed. We need a better understanding of what's happening, which is why we've issued this alert," Dr. Gayane Hovhannisyan, the associate medical officer of health, said in a statement. 

In many ways, this is maddening. 

Why don't we care about infectious diseases until they start to affect school children, university students and the suit-and-tie wearing members of society?  

The reality is that almost every infectious-disease outbreak – from annual influenza through to pandemics like AIDS – strikes the vulnerable first. That's how it gains a foothold to wend its way into the general population. 

In other words, there is a great deal of self-interest in doing better health surveillance, and providing better health care, to members of marginalized communities such as the homeless, drug users and sex workers. 

But we do the exact opposite. 

Overcrowded shelters, for example, create the ideal conditions for the spread of disease. That's why the outbreaks of iGAS were concentrated at the Salvation Army Centre for Hope in London, Seaton House in Toronto and Old Brewery Mission in Montreal.

Vietnam: Seven dialysis patients die in a hospital in one day

Via Saigon Giai Phong: Seven dialysis patients die in a hospital in one day. 

While on dialysis in the hospital on May 29, 18 patients with kidney failure had anaphylactic shock and six of them succumbed to the shock on the same day. [A seventh patient died after the others--CK] 

Informed of the incident, the Ministry of Health sent a mission team led by Luong Ngoc Khue, head of the health ministry’s Medical Examination and Treatment Department to probe the incident.   

At present, 11 patients in the incident are transferred to Bach Mai Hospital in Hanoi for further treatment.  Director of the General Hospital in Hoa Binh Province Truong Quy Duong said that 18 patients arrived at the hospital for dialysis treatment as scheduled yet they had the shock after 30 minutes later; accordingly, medical workers stopped dialysis treatment and provided intensive treatment; however, at 5PM six of them died.  

Director Duong said that currently, causes of the incident have not been verified yet. The hospital has asked for assistance from Hanoi-based Bach Mai Hospital which advised not to transfer patients for a long distance while they are in shock so the central hospital instructed their colleagues how to treat patients with anaphylactic shock in Hoa Binh Hospital yesterday.  

All fluids for transfusion and drugs in the incident were kept for investigation. Police were quick to come to the hospital to liaise with the hospital managers for verifying the incident’s cause. 

Deputy Prime Minister Vu Duc Dam arrived in the General Hospital in Hoa BInh to visit and offered condolences to relatives of patients in the incident. He asked the Ministry of Health, the Department of Health in Hoa Binh Province and Bach Mai Hospital to mobilize all resources to treat these patients.   

The Ministry of Health asked the General Hospital in Hoa Binh to stop dialysis treatment and set up a scientific council to verify the cause of the incident and issue penalty on team or individual who had mistakenly committed wrongdoing.  

More than 100 people with kidney failure usually receiving dialysis in the General Hospital in Hoa Binh Province were transferred to Hanoi for continued treatment.  

After the incident, police seized all machines, equipment and medications of the Renal Ward of the General Hospital in Hoa Binh Province. The hospital stopped carrying out the dialysis to wait for conclusion. Province administrators gave VND5 million and hospital managers gave VND10 million to each relative of dead patients.

UN: A "rapidly unfolding" health disaster in Gaza

Via ReliefWeb, an August 2 report from WHO, UNRWA, and OCHA: United Nations warns of “rapidly unfolding” health disaster in Gaza. Click through to download the PDF, but here is the complete statement:

A health disaster of widespread proportions is rapidly unfolding in the Gaza Strip as a direct result of the ongoing conflict, said the United Nations today. 

Mr. James W. Rawley, the Humanitarian Coordinator in the occupied Palestinian territory (oPt), together with Mr. Robert Turner, UNRWA’s Director of Operations in the Gaza Strip, and Dr. Ambrogio Manenti, acting Head of Office of WHO’s operations in the West Bank and Gaza Strip, expressed grave concern regarding the lack of protection for medical staff and facilities, and the deteriorating access to emergency health services for the 1.8 million Palestinians in the Gaza Strip. 

“We are now looking at a health and humanitarian disaster”, warned Mr. Rawley, adding, “the fighting must stop immediately”. 

After more than three weeks of intense conflict, Gaza’s medical services and facilities are on the verge of collapse. 

One third of hospitals, 14 primary healthcare clinics and 29 Palestinian Red Crescent and Ministry of Health ambulances have been damaged in the fighting. 

At least five medical staff have been killed in the line of duty and tens have been injured. 

At least 40% of medical staff are unable to get to their places of work such as clinics and hospitals due to widespread violence and at least half of all public health primary care clinics are closed. 

In addition, in the last 24 hours, anonymous calls were made to staff at both the Najjar Hospital in Rafah and Al Shifa Hospital in Gaza City warning of imminent attacks, causing major panic and chaos among patients and staff. Najjar Hospital was evacuated and remains closed due to fighting nearby. 

The hospitals and clinics that are still functioning are overwhelmed: since 7 July over 8000 people have reportedly been injured, many seriously. Critical supplies of medicines and disposables are almost depleted and damage and destruction of power supplies has left hospitals dependent on unreliable back-up generators. Al Shifa, the main referral hospital in the Gaza Strip, is inundated with casualties and people seeking safety in its grounds. 

“The ability to provide necessary heaalthcare is being severely compromised. This puts the lives of thousands of Palestinians in needless danger”, said Dr. Manenti. 

An estimated 460,000 people have been displaced and are now living in overcrowded conditions in schools, with relatives or in makeshift shelters. This, coupled with lack of inadequate water and sanitation, poses serious risks of outbreak of water-borne and communicable diseases. 

“Hundreds of thousands of people are sheltering in terrible conditions, pushing UNRWA’s coping capacity to the edge”, said Mr. Turner. 

Mr. Rawley stressed that “international law sets out clear obligations on the parties to the conflict to respect the status of hospitals and medical facilities as protected objects, to respect the status of and ensure the protection of medical personnel, to ensure the protection of civilians and to respect the fundamental human right to health ". 

The three officials also paid tribute to Gaza’s medical staff for working tirelessly in dangerous and difficult conditions to continue to provide urgently needed healthcare.

Health consequences of the latest Gaza shelling

Via ReliefWeb, an AFP report: UN fury over new deadly strike on Gaza school - occupied Palestinian territory. After describing the strike on a UN school and the international response, the report continues:

• Hospitals in crisis - 

At the school, an AFP correspondent witnessed scenes of chaos, with rescuers trying to evacuate the wounded, adults sprinting frantically away through pools of blood, young children clutched in their arms. 

With hospitals and clinics under increasing pressure, Gaza's medical services have reached the brink of collapse, the UN warned. 

Rafah's main Najjar hospital is closed after being hit and only two clinics were functioning, with medics rapidly running out of space to store bodies. 

In one, an AFP correspondent saw the bodies of four small children packed into an ice cream freezer. 

Outside in the garden, doctors had set up a temporary emergency room, receiving dozens of wounded, some of whom had to lie on the ground because there were no beds, he said. 

There was only one working operating surgery, with the single bed occupied by two wounded people, he added. 

Intensive international attempts to broker a diplomatic end to the fighting between Israel and Hamas have so far proved fruitless, but the efforts are continuing with a Palestinian delegation in Cairo for talks with US and Egyptian officials. 

Ministers in Israel's security cabinet decided not to send a representative.

UK: WHO's child shock guidelines 'are deadly'

Via BBC News: Child shock guidelines 'are deadly'. Excerpt:

Thousands of children could be dying each year because the World Health Organization has not updated guidelines for treating those going into shock, UK researchers warn. 

They say the advice to give large quantities of fluid is deadly. 

The updated guidelines in 2013 did not recommend a change, which the researchers described as "disappointing and puzzling". The WHO said it had to be "very vigilant" when changing guidelines. 

And that it aimed to publish a new set of interim guidelines by early 2015.

Disagreement 

Critically ill patients can go into shock as a result of severe infections, such as malaria, or fluid loss. It changes the way blood flows around the body leaving patients looking pale. 

The recommended treatment is "rapid fluid resuscitation" - a large injection of fluid via a drip. 

This brings children out of shock, but a large study on children in Africa in 2011 suggested it was also deadly. 

Three more children out of every 100 treated would die with fluid resuscitation when compared with those slowly given small quantities of fluid, the study indicated. 

In those with the most severe shock, 48% died with the resuscitation compared with 20% given the low fluid doses, it suggested. Prof Kathryn Maitland, a paediatrician with the Medical Research Council and Imperial College London, criticised the WHO for not changing guidelines in its latest update. 

She told the BBC: "We're very concerned that two and a half years later the guidelines have not changed." 

Thousands dying 

She said there was a lack of data on the precise number children being diagnosed with shock. 

But she added: "We can be confident that if hospitals follow the guidelines, there will be excess mortality... it is likely to run into thousands."