Hemolytic Anemia in an Adult.

There are three patients that you have been asked to manage.

Patient 1. This patient is in the hospital for a review of his blood pressure and cardiac status. He is 68 year old retired college lecturer whose only complaint is that he cannot cope with his daily routine. You ask him what his daily routine is and he says “I do the grocery shopping for my wife, go to the mosque for my morning and evening prayers,  read books, write an article for the newspaper or magazine. I have stopped my evening walk, I used to walk for 3 miles but now I get too tired.”

You examine him and except for significant anemia and a firm spleen which is 2 cm enlarged below the costal margin you find no abnormality. He has no jaundice, has not lost weight recently and his appetite is not decreased.

What questions will you ask him? Does he have angina or shortness of breath when he walks. Has he vomited blood or had black granular material in the vomit or has he passed soft, sticky  black stools. Does he have heartburn? Has he had jaundice in the past and has he ever tested positive for hepatitis B or C? He gives a negative answer to all these. A blood study shows anemia, neutropenia, thrombocytopenia. There are 5% blast cells in the blood. A bone marrow exdamination was requested.

What does this patient have?

A myelodysplastic syndrome which shares clinical and pathologic features with acute myeloid leukemia (AML), but MDS has a lower percentage of blasts in peripheral blood and bone marrow (by definition, <20 percent). Patients with MDS are at risk for symptomatic anemia, infection, bleeding, and transformation to AML, the incidence of which varies widely across MDS subtypes.

Patient 2.  This patient is a 44 year old housewife who has come for evaluation for backache, abdominal pain and jaundice. She feels very tired and has had a tinge of jaundice for the past 4 days and has noticed that her urine is dark coloured. On examination she has anemia, jaundice and hepatomegaly of two cm and a spleen of 4 cm, both are soft and difficult to feel.

What questions will you ask her?

What medicines has she recently used? She was given ciprofloxacin for a UTI ten days ago. It is possible for ciprofloxacin to cause hemolytic anemia. Her direct antigen test (Coombs test) was positive for IgG. She seems to have reacted to ciprofloxacin.

The clinical presentation  in severe hemolysis, patients may experience sudden onset of pallor, fatigue, jaundice, and in some cases dark urine, abdominal pain, or back pain. Typical symptoms of hemolytic anemia include those associated with anemia (fatigue, weakness, dyspnea, symptoms related to volume depletion like fainting and lightheadedness or vertigo) as well as hemolysis (jaundice; in some cases dark or red urine due to hemoglobinuria).

The Berlin Case-Control Surveillance Study from 2011, which included 134 cases of drug-induced autoimmune hemolytic anemia (AIHA), mostly in an outpatient setting, reported commonly implicated drugs to include beta-lactam antibiotics such as piperacillin, ceftriaxone, cotrimoxazole, ciprofloxacin, fludarabine, lorazepam, and diclofenac and anticancer drugs. Oxidant injury can be caused by dapsone, primaquine and phenazopyridine.

Drugs tend to cause immune reactions in the following ways.

  • Penicillin like reaction. The drug induces antibodies. So long as the drug coats the RBC the antibodies will react against it. Stopping the drug will reduce the reaction and eliminate it in the time taken to eliminate the drug from the system.
  • Immune complex reaction. The drug induces immune complexes which react against the RBCs and activate complement which causes the hemolysis. Just stopping the drug will not eliminate the reaction. The antigen complexes have to be metabolised for the reaction to be stopped and will take a longer time for recovery.
  • Passive absorption. In the passive absorption type, administration of antibody preparations introduces antibodies that can react with the recipient’s RBCs. Intravenous immune globulin (IVIG) or Rho(D) immune globulin frequently contain allo-antibodies that react with the recipient’s RBC antigens (eg, anti-D, anti-A, or anti-B) producing alloimmune hemolysis.
  • Alteration of RBC surface antigen – In this type of reaction, the drug alters a normal membrane component of the RBC membrane. It can cause immune hemolysis several weeks to months after drug initiation. The DAT (direct Coombs) test is positive.

A great number of drugs cause Auto-Immune-Hemolytic Anemia (AIHA) including aspirin, acetaminophen, chlorpropamide, ciprofloxacin etc.

Patient 3. A 20 year old soldier who recently went home to the interior of Sindh for his summer leave for one month. He comes back feeling very tired and unable to cope with the PT and parade practice which is the daily  routine in his regiment. He fainted once when the sargent forced him to run. He has noticed a tinge of jaundice and  dark colored urine. You find that he is markedly anemic, has a lemonish tone of jaundice, has an enlarged, hard spleen about 8 cm below the costal margin. The liver is not enlarged and he has no stigmata of chronic liver disease.

What questions will you ask him? Has he had episodes of jaundice in the past, or has he needed a blood transfusion? Has he got a family member specially a sibling who has episodes of jaundice? Did he have fever while he was on leave? Has a family member ever been told that their spleen was enlarged or ever needed a blood transfusion? on asking he says that he had fever with rigors twice during the month he was on leave. The doctor in the small town where he lives told him it was malaria and treated him for it. He says that every one in his home town suffers from malaria fever several times in the summer. His younger brother has been told he has an enlarged spleen. His parents are first cousins and he is engaged to his first cousin as the family always marry other close family members.

What are we chasing? A hemoglobinopathy which unlike  thalasemia presents in early adulthood: HbD disease, HbE disease, HbC disease or an RBC membrane disease like congenital spherocytosis, elliptocytosis, stomatocytosis. Remember the these can be combined like HbD with thalasemia trait or thalasemia beta minor or with spherocytosis. These are very much present in Pakistan so much so that HbD is also known as Hemoglobin Punjab disease.

This patient had a hemoglobin of 6gm/dl. He needed 3 blood transfusions to raise his hemoglobin to 9.8 gm/dl. Why did his hemoglobin drop to this level suddenly? In addition to the condition causing his hemolysis he had 2 episodes of malaria in which the hemoparasite causes hemolysis as well.

Patient 1 had a hemoglobin of 10 gm/dl and patient 2 had a hemoglobin of 8.5 gm/dl. How will you determine that these patients are hemolysing their blood? In all patients who are anemic without any evidence of bleeding from anywhere hemolytic anemia should be suspected. The reticulocyte of 6% or between 6 to 10% is proof of ongoing hemolysis unless the patient has had a recent bleed or been given nutrients like iron, folic acid or B12. Remember reticulocytes have a survival of 4 days; 3 days in the bone marrow and 1 day in the systemic circulation.  Next measure the haptoglobin; in hemolysis it will be low. The LDH will be high and so will the serum bilirubin.

The next is the blood smear. The blood smear will show abnormalities in the RBCs like broken cells or schistocytes, spherocytes; round cells with no pallor in the centre and a smaller size than normal discoid RBCs and on, Heinz bodies may be present on the cells.

Patient number 3 had spherocytes and fragmented cells and on hemoglobin electrophoresis HbD was detected so his diagnosis was hereditary spherocytosis and HbD disease. His younger brother was also investigated and carried both the diseases. Both were advised splenectomy as the destruction of the RBCs takes place in the splenic cords and the survival time of the RBCs can be increased by removing the spleen. Hemolysis will be reduced though not eliminated.

What does the consistency of the spleen (and liver) tell us? A firm spleen means that the spleen has been enlarged for some months, a soft spleen tells you about recent enlargement of the organ and a hard spleen tells you about a spleen that has been enlarged for many months or years even.

When should a direct Coombs (direct antigen test or DAT) test be done?

A DAT should be obtained in all patients who present with anemia, laboratory evidence of hemolysis (ie, increased lactate dehydrogenase, increased indirect bilirubin, reduced haptoglobin), and an absence of schistocytes on the peripheral blood smear.

The direct antiglobulin test (DAT; direct Coombs test) is performed by adding anti-human globulin to patient RBCs. The immune globulin is on the patient’s RBCs. The indirect antiglobulin test (IAT; indirect Coombs test) is performed by adding patient plasma to test RBCs followed by the addition of anti-human globulin. In either case, the presence of an anti-RBC antibody (autoantibody or alloantibody) causes RBCs to be agglutinated when the anti-human globulin is added. In the indirect test the antigen is in the patient’s plasma.

Patient number 2 had a history of intake of ciprofloxacin which could have caused hemolysis. She was negative for RA factor but positive for anti-dsDNA antibodies. The possibility of AIHA was raised. It is important to distinguish between warm-AIHA and cold agglutinin disease, which is typically caused by IgM autoantibodies that react with polysaccharide antigens on red cells at temperatures below core body temperature and result in RBC agglutination  and complement-mediated hemolysis. In cold agglutinin disease, the DAT is typically negative for IgG but positive for C3 fragments.

What does pink serum, positive serum free hemoglobin, positive urine dipstick for heme, positive urine for hemosiderin indicate? It points to intravascular hemolysis rather than in the reticuloendothelial system and may indicate one of the following conditions;

  • AHTR (acute hemolytic transfusion)
  • Overwhelming bacterial infection (eg, from clostridium perfringens)
  • Paroxysmal nocturnal hemoglobinuria (PNH)
  • Paroxysmal cold hemoglobinuria (PCH)

Let us examine some unusual situations.

Is it possible to have hemolysis without reticulocytosis?

Hemolytic anemia can be seen in the absence of an appropriate reticulocyte response, often resulting in a more profound degree of anemia. This occurs when the bone marrow is not capable of responding appropriately to anemia. If hemolysis is suspected or confirmed but the reticulocyte count is inappropriately low, there are several possible concomitant conditions that may be responsible for blunting the reticulocyte response: such as iron deficiency anemia, vitamin B12 or folate or copper deficiency, alcohol induced anemia, anemia of chronic inflammatory disease or myelodysplastic syndrome, drug induced bone marrow suppression and temporary bone marrow suppression as in parvovirus disease.

Hemolysis without anemia

Hemolysis without anemia can be seen if the bone marrow capacity to increase RBC production is sufficient to overcome the anemia caused by the hemolysis.

Reticulocytosis without hemolysis

A patient thought to have hemolytic anemia based on an increased reticulocyte count may in fact have another cause of reticulocytosis. They may be  recovering from an episode of bleeding or ongoing bleeding or may have been deficient in a nutrient which has been repleted such as iron, vitamin B12, or folate; been administered erythropoietin or is recovering from a bone marrow insult such as an infection (eg, parvovirus), medication, or alcohol.

What you need to know about inherited hemolytic anemia in an adult with splenomegaly and no stigmata of thalasemia.

You have found an enlarged spleen, a tinge of jaundice and anemia in a twenty year old adult.

What will you look for next? How will you start the discussion in a short case?

You will look for and discuss the stigmata of beta thalassemia major underlined below.

Children have a short stature, frontal bossing, non-aeration of the maxillary sinuses, overriding of the upper jaw, irregular teeth with a narrow mouth, osteoporosis with long bone deformities, vertebrae and ribs become box-like and prone to fractures. Bone masses resembling tumors develop but these masses are non-invasive.

Why does hemolysis occur in thalasemia? The inherited abnormality in the genes which causes the disease results in the unbalanced production of alpha and beta hemoglobin genes. The unpaired chains precipitate out and cause hemolysis. This results in transfusion dependent anemia and the production of hematopoietic masses and in beta thalassemia major a dependence on blood transfusions develops from early life (2 years of age). Iron overload is a major problem naturally but is made worse with recurrent blood transfusions.Your patient has none of these abnormalities, has achieved normal height according to the population he comes from. He has only recently become sufficiently anemic to need blood transfusions over the past one year. His spleen is 18 cm enlarged. His liver is not enlarged and the liver span is normal.
How will you open the discussion?
You can say in my opinion my patient has an inherited a form of hemolytic anemia like beta thalassemia minor or intermedia or an inherited hemoglobinopathy or a red cell membrane defect like spherocytosis or elliptocytosis.  I do not have the family history (in a short case) but I would like to ask about the health of his other siblings and whether his parents are first cousins. In a long case give a history of blood transfusions or lack thereof, a family history and a history of consanguinity in the parents.
I do not think it is thalassemia major because of the late onset of transfusion dependency and absence of bone deformity and because of his normal average height. He most probably has beta thalasemia minor or intermedia or an acquired hemolytic anemia or another hemoglobinopathy.
He may have other hemoglobinopathies like Hb H which is inherited as an autosomal recessive gene and sometimes Hb S, sickle cell anemia (uncommon in the Pakistani population) and Hb D (also known as Hb Punjab) which may occur alone or accompany thalasemia.
The other possibility is congenital spherocytosis or elliptocytosis. I would place sickle-cell anemia low in the list of D/D as it is uncommon in the Pakistani population and may be found in people of Makran origin.
Discus the acquired hemoglobinopathies next. See my spot on acquired hemolytic anemias.
Inherited hemoglobinopathies. Questions you are likely to be asked.
What is the composition of the different hemoglobins?
HbA has 2 alpha 2 beta chains, HbA2 has 2 alpha and 2 delta chains and constitutes 2.5% of all hemoglobin, HbF (fetal) has 2 alpha and 2 gamma chains. Hb beta has 4 beta chains and HbBarts has 4 delta.
HbS has 2 alpha 2 beta chains but there is a mutation causing a change from glutamic acid to valine on one beta chain. HbS is resistant to hemolysis by malignant tertian malaria.
HbC and HbE have a change from glutamic acid to lysine but on different beta chains.
HbD has a a change from glutamic acid to glutamine. These changes in their composition makes them liable to hemolysis.
What are the qualities of normal hemoglobin?
It is soluble in the RBC, takes up and releases large quantities of oxygen and acts as a buffer.
Why does hemoglobin S cause a problem?
It has the same oxygen carrying capacity as HbA1 but only 20% of the solubility. It forms long strands which settle in the RBC and change its shape to that of a sickle which is liable to stick inside the capillaries causing micro-infarcts and also causes hemolysis. The lifespan of a sickle cell is 10-20 days hence the anemia. Don’t start your discussion with sickle cell anemia as it is very rare in Pakistan (OR find out if it is common in your area) or if your patient gives a history suggestive of bone or organ infarcts or a suggestive ancestry.
What is Hb SC?
This is hemoglobin S and hemoglobin C occurring together. The patient has 40% HbS, 40% HbC and 20% HbF in their RBCs.
What is Hb D disease? It is also known as Hb D Punjab.
The variant Hb D can be found as a mild hemolytic disease in North India, Pakistan, Iran and African Americans or in combination. It occurs in 4 forms homozygous Hb D disease, heterozygous Hb D trait, Hb D-thalasemia and Hb D-HbS disease. The homozygotes present as mild hemolytic anemia and moderate splenomegaly.
Hb E disease.
This is the most common hemoglobin abnormality found in the world. It is commonly found in Southeast Asia specially Thailand. It is inherited as an autosomal recessive gene. Presents as asymptomatic mild anemia. Its beta chain synthesises more slowly.
Hb Constant Spring.
The recessive gene produces a long, unstable alpha chain which has 31 extra molecules. Presents as anemia with a low hemoglobin in RBCs.
Hemoglobin C. (named after Christchurch in New Zealand)
This is the commonest hemoglobin variant found in the USA. This mutation reduces the normal plasticity of host erythrocytes. Hb C crystallizes in the RBC, due to decreased solubility. RBCs become more rigid, often fragment (microspherocytes form) as they attempt to transverse microvasculature. RBC life-span is 30-35 days. Hb composition:- Hb C >90%, Hb F <10%Prevalence. The Hb C mutant allele is common in West Africa; found in I%of African Americans. Genetic compounds (heterozygotes for both HbS and C or thalassemia) are not infrequent, due to significant geographic overlap. Clinical Symptoms: splenomegaly (from sequestration of rigid cells), mild-to-moderate normocytic, normochromic anemia(Hb level 8-12 g/dL). In homozygotes, nearly all Hb is in the Hb C form, resulting in moderate normocytic normochromic anemia. In those who are heterozygous for the mutation, about 28-44% of total Hb is Hb C and anemia does not develop(it is considered a benign condition)
Thalasemia.
This is an autosomal recessive gene found in Cyprus 16%, Thailand 3-14%, 3-8% in India, Pakistan, Bangladesh and China and also Southeast Asia and Africa. When the abnormality is in the production of the alpha gene it is called alpha thalasemia and when in the beta chain it is called beta thalasemia. The mutation slows down the production of the affected chain so tetramers of the healthy chain form Beta 4, alpha 4 or gamma-4. These accumulate in the nucleus and stop cell division. Many cells die in the bone marrow, those released into the circulation sequester in the spleen.
Patients do not become symptomatic while they are producing fetal hemoglobin that is upto the age of 2 years when the adult type of hemoglobin is phased in.
Complex thalasemia is fortunately, much less common. Involves large deletions from the beta-globin gene cluster. If at least one of the gamma genes is still intact, Hb F will persist after birth.
Hereditary Persistence of Fetal Hemoglobin.
Fetal Hb (Hb F) is the main oxygen transport protein in the fetus during the last 7 months of development. Hb F binds oxygen with greater affinity than the adult form. Hb F is nearly completely replaced by Hb A by approximately the 12th week of postnatal life. Decreased~-globin chain synthesis is compensated for by the production of gamma-globin. Homozygotes have 100% Hb F. Heterozygotes have 70 % Hb A and 30 % Hb F.
Your patient may also have an acquired hemoglobinopathy. This will be discussed in another post.
Would you consider splenectomy in this patient?
If the survival of transfused RBCs is short so that he develops anemia soon after a blood transfusion and progressive worsening of the anemia along with other cytopenias are indications that hypersplenism has developed and that it may be appropriate to evaluate the patient for splenectomy.
What other treatment would you consider to make this patient free of transfusions and prevent him from suffering the consequences of iron overload?
I would consider hematopoietic bone marrow transplant. A two haplotype HLA matching preferably sibling donor will be required. The cost is prohibitive about 4 million rupees are required. The major problems encountered in a bone marrow transplant are the difficulty in finding a matching donor as parents are not suitable as they are only one haplotype match, the occurrence of graft versus host disease and the prohibitive cost.
Why do normal RBCs die eventually? Remember they have a lifespan of 120 days only.
They encounter oxidative trauma from oxygen and its products, shear pressure while traveling through the splenic cords and aortic valves, osmotic changes encountered repeatedly in the lungs (hypo-osmolarity) and kidneys hyperosmolarity), loss of enzymes and slow development of a spherical shape with age.
How do you assess the severity of on going hemolysis?
Historically radiolabelling of RBCs with CR 51 and differential agglutination and
The evidence of persisting hemolysis are : a high retic count of >6 at any time or persistent retic count of 10, or a low haptoglobin levels and if the LDH levels and serum bilirubin (indirect) are high. The Hb will be low and the MCV low around 65 ftl.
Why does iron overload develop even when the patient has minimal or no blood transfusion requirement?
Persistent inadequate hematopoiesis and continual breakdown of RBCs releases iron into the circulation causing it to be stored in parenchymal sites such as the liver and spleen.
What vitamin and metal deficiencies may occur in thalassemia?
The patient requires folate, B12, zinc supplements.
Can you measure RBC life span?
Yes but the techniques are not used clinically. Labelling RBCs with Biotin and radio active chromium 51 have been used to determine the site of RBC destruction and their life span in research. Another method is differential aggregation of a cohort of RBCs. It is possible to calculate RBC life span from the formula:

RBC survival (days) ≈ 100 ÷ [Reticulocytes (percent) ÷ RLS (days)].

RLS is reticulocyte survival and is approximately 4 days; 3 days in the bone marrow and one day in the circulation

Alpha thalasemia major is severe and causes hydrops fetalis and despite in utero blood transfusion death usually occurs in utero or soon after birth.

 

Prof Shaheen's Tutorials in Medicine

You have found an enlarged spleen, a tinge of jaundice and anemia in a twenty year old adult.

What will you look for next? How will you start the discussion in a short case?

You will look for and discuss the stigmata of beta thalassemia major underlined below.

Children have a short stature, frontal bossing, non-aeration of the maxillary sinuses, overriding of the upper jaw, irregular teeth with a narrow mouth, osteoporosis with long bone deformities, vertebrae and ribs become box-like and prone to fractures. Bone masses resembling tumors develop but these masses are non-invasive.

Why does hemolysis occur in thalasemia? The inherited abnormality in the genes which causes the disease results in the unbalanced production of alpha and beta hemoglobin genes. The unpaired chains precipitate out and cause hemolysis. This results in transfusion dependent anemia and the production of hematopoietic masses and in beta thalassemia major a dependence on…

View original post 1,591 more words

What you are expected to know about COVID-19 virus

What will another professional, who is assessing you for an examination or a job application expect you to know about the current coronavirus, COVID-19 or SARS-COVID-19? I have put down some general knowledge about viruses and the corona viruses in particular. As information about the corona virus which is causing the disease we now recognize as COVID-19 is novel and about which the medical profession is learning even as it is expected to fight the disease, I have put down some studies which we should all be familiar with. Most of these are taken from Journal Watch NEJM.

  1. What is a virus? It is a non-cellular form of living organism which requires a cellular living organism to replicate and produce the enzymes it needs for survival. The cell the virus enters, dies eventually as its own functions are disrupted by the virus, which takes over it’s DNA either directly or through a reverse transcriptase.
  2. How are viruses classified? There is extensive classification of viruses. Clinically we recognize them from the diseases they cause or as DNA or RNA viruses from the genetic material they carry and with which they take over the cell nucleus and its synthetic functions. They are also classified according to their shape; helical, or icosahedral or a single or double strand; whether they have an envelope or are naked.
  3. What does the Corona virus look like? The corona viruses are a spherical or pleomorphic enveloped particles containing single-stranded (positive-sense) RNA associated with a nucleoprotein within a capsid comprising a matrix protein. The envelope bears club-shaped glycoprotein projections. These club shaped structures give it the appearance of a crown hence the name corona. The COVID-19 has an icosahedral shape wrapped in a protein shell with the characteristic club shaped projectiles forming a corona . The genome size of corona viruses ranges from approximately 26 to 32 kilobases, one of the largest among RNA viruses.
  4. Is there a life form smaller than a virus? Subviral organisms exist.
  5. What diseases do the coronaviruses cause? Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans, these viruses cause respiratory tract infections that can range from mild to lethal. Mild illnesses include some cases of the common cold (which is caused also by certain other viruses, predominantly rhinoviruses), while more lethal varieties can cause SARS, MERS, and COVID-19. Symptoms in other species vary: in chickens, they cause an upper respiratory tract disease, while in cows and pigs they cause diarrhea. There are as yet no vaccines or antiviral drugs to prevent or treat human coronavirus infections.
  6. Why is the corona virus likely to mutate? RNA viruses lack the the proofreading function. The host exoribonuclease nonstructural protein, provides extra fidelity to replication by providing a proofreading function which the RNA-dependent RNA polymerase lacks. If the host does not form the protein which does the proofreading the virus will mutate.
  7. What is the effect of mutation of the virus? Vaccines which are in use become ineffective and new vaccines have to be developed according to the current form of the virus as the antibodies in a person no longer recognize the new virus.
  8. Once infected how long does the acquired immunity last in a subject? The immunity may last for 1 to 2 years. That is why there is a fear of a second wave of COVID-19 infection next year.
  9. How is the corona virus which causes Covid 19, SARS, MERS spread in humans and animals? Coronaviruses mainly target epithelial cells. They are transmitted from one host to another host, depending on the coronavirus species, by either an aerosol, fomite, or fecal-oral route. Human coronaviruses infect the epithelial cells of the respiratory tract, while animal coronaviruses generally infect the epithelial cells of the digestive tract. Covid 18 and SARS coronaviruses, for example, infect via an aerosol route and fomite route, the human epithelial cells of the lungs by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. ACE2 is a membrane-bound aminopeptidase found ubiquitously in humans and expressed predominantly in heart, intestine, kidney, and pulmonary alveolar (type II) cells. Entry of SARS-CoV-2 into human cells is facilitated by the interaction of a receptor-binding domain in its viral spike glycoprotein ectodomain with the ACE2 receptor.

In an effort to prevent the spread of SARS-CoV-2, the transmission of the corona virus has been studied keeping its similarity to the SARS and MERS virus.

If it acts like the SARS coronavirus, the MERS coronavirus, and other respiratory viruses, SARS-CoV-2 would spread primarily through large droplets and environmental contamination. However, several studies suggest transmission by the aerosol route. An aerosol is a suspension of fine solid or liquid particles in gas smoke, fog, and mist form. Commercially an aerosol is dispensed as a payload propelled through a fine hole from a can containing a propellant gas. In a patient bronchial secretions are propelled through an almost closed mouth by the forceful contraction of the muscles of the chest wall, The mist which emerges from the mouth contains the viral particles. The mist particles are smaller than droplets, propelled further and remain suspended in the air longer hence have a greater capacity to transmit the virus. These particles are deposited on the surface of furniture, counter tops and work surfaces and remain viable and highly infective as fomites. Studies have been published in the reference journals given below and a Chinese study quoted in detail as well.

(NEJM JW Infect Dis May 2020 and N Engl J Med 2020; 382:1564; NEJM JW Infect Dis Jun 2020 and Nat Med 2020 Apr 2; [e-pub], and Ann Intern Med 2020 Apr 6; [e-pub]).

Investigators from Wuhan, China, now report the results of air sampling in and around two hospitals designated for COVID-19 patients.

Relatively little viral RNA was found in air samples from negative-pressure isolation rooms, intensive care unit (ICU) rooms, or ward rooms in a tertiary-care COVID-19 designated hospital. Deposition of 31 and 113 copies per meter2 per hour was found on two surfaces in ICU rooms. In contrast, in a temporary field hospital, low levels of viral RNA were found in air samples from general patient care areas and from a portable toilet unit. Three air samples from protective apparel removal rooms in the field hospital had from 16 to 42 viral RNA copies per meter3; most particles were 0.25 to 1 μm in size. After intense sanitization in the field hospital, air samples had no viral RNA. Most air samples from public areas near the two hospitals were negative; one from a crowd-gathering site near a department store entrance by the tertiary-care hospital had 11 copies per meter3, and one just outside the hospital entrance had 7 copies per meter3. This report provides real-world evidence of SARS-CoV-2 RNA suspended in submicrometer particles in the air and deposited on surfaces in two hospitals. The investigators did not test whether the sample viruses were infectious or provide direct evidence of airborne transmission. Still, the findings raise further concern that airborne transmission might be contributing to the rapid spread of COVID-19 and support intensive disinfection of bathrooms and areas where protective apparel is doffed; they also support wearing face masks in public areas.

9. What symptoms does the virus cause?

The COVID-19 virus may cause mild to moderately severe flu like symptoms but with a tendency to cause high fever. Because of its proclivity for the ACE-2 in the lungs it causes acute inflammatory pulmonary edema, the Severe Acute Respiratory Syndrome, requiring the use of an invasive ventilator. It also has has a tendency to attack people with previous heart disease with severe consequences. About 20% of patients have an acute decline in the renal functions and may require the attention of a nephrologist. A patient may present with vomiting and diarrhoea from having contracted Covid 19 without respiratory symptoms. In patients with Covid 19 there is a tendency for strokes to occur especially in younger patients because of platelet dysfunction and tendency to clot. In older patients a wide variety of neurological symptoms occur which cannot be directly linked to the virus itself.

Are outpatient physicians susceptible to acquiring COVID-19 from their patients?

More studies will come in later but I quote one survey from Italy where the disease was widely rampant. Office-based physicians have not been as visible in COVID-19 news coverage as hospital staff, although outpatient clinicians clearly are affected by similar safety and volume issues, all without the support structure a hospital provides. How are they faring? A survey that was sent in February and March 2020 to 450 Italian primary care physicians affiliated with a single hospital in Lombardy (the hardest hit region of Italy) provides a glimpse.

Of 272 respondents (60% response rate) who were providing care to an estimated 400,000 patients, about half reported at least one known contact with a SARS-CoV-2 patient. Almost all had tried to prevent overcrowding in the office, and about 90% had modified their practice to include phone-based care or telemedicine. Most had purchased their own personal protective equipment (PPE), less than half had received PPE from the Ministry of Health (the employer of Italian physicians), and less than 20% had provided PPE for use by waiting patients.

About 40% reported that they themselves had experienced cough, fever, or gastrointestinal symptoms during the preceding 4 weeks; symptoms lasted for longer than 1 week in about half who were ill. Only 18 respondents were tested for SARS-CoV-2; only 2 tests were positive. These data (skewed, of course, to a set of primary care doctors with the time and, presumably, the health to respond to a survey) are notable for high rates of preparation and very low rates of testing, despite a sizable prevalence of suggestive symptoms. The authors note that, when they wrote this report, 20 primary care physicians in the region had died of COVID-19.

11. Do the ACE-I or ARBs make the prognosis worse if the patient has COVID-19?

Mancia and colleagues studied 6272 people (age, ≥40) with SARS-CoV-2 infection from the Lombardy region of Italy and 30,759 uninfected controls matched by age, sex, and residence. Infected patients more commonly used ACE inhibitors and ARBs than controls. However, after multivariable adjustment, these medications were not associated with infection or severe disease.

Hypertension, Medications, and COVID-19 Risks
Harlan M. Krumholz, MD, SM reviewing Mehra MR et al. N Engl J Med 2020 May 1 Reynolds HR et al. N Engl J Med 2020 May 1 Mancia G et al. N Engl J Med 2020 May 1

Are children more susceptible to COVID-19?

A review of published pediatric cases of confirmed SARS-CoV-2 infection shows largely mild disease.

Most COVID-19 cases are in adults, but we are gaining data on the clinical effects of the virus in children (NEJM JW Pediatr and Adolesc Med Apr 2020 and MMWR Morb Mortal Wkly Rep 2020 Apr 10; 69:422). These investigators conducted a systematic review of articles published between December 1, 2019, and March 3, 2020, that included children ≤19 years of age with confirmed SARS-CoV-2 infection. They identified 17 studies from China and 1 from Singapore, which included 1065 cases. Findings include:

444 children were aged <10 years and 553 were aged 10 to 19 years (age was not provided for some). Most children acquired infection after close contact with infected family members.

Clinical presentation was mild in all cases, with the exception of one infant who had a severe presentation and required intensive care. Fever, dry cough, and fatigue, as well as nasal congestion and rhinorrhea, were the most commonly reported symptoms; gastrointestinal symptoms were noted in infants. Similar to findings in adults, radiographic findings included bronchial thickening, ground-glass opacity, and evidence of pneumonia. Although limited information on therapeutic interventions was available, only one patient required respiratory support, including oxygen therapy. One death was reported in a child in the age range 10 to 19 years, but the children otherwise recovered uneventfully.

This review suggests that infected children have mild symptoms and are not likely to require hospitalization or intensive care. We do not know the role infected children play in community spread of the virus. With new information emerging about a possible connection between SARS-CoV-2 infection and a condition that resembles Kawasaki toxic shock syndrome, it is clear there is still much more to learn about this virus.

(COVID-19 in Children and Adolescents in China and Singapore
Deborah Lehman, MD reviewing Castagnoli R et al. JAMA Pediatr 2020 Apr 22)

Does C0VID-19 affect the sense of smell and taste?

Two thirds of patients with mild COVID-19 reported alterations in their sense of smell or taste. A phone survey was completed by 202 out of 283 patients who were contacted, in Lombardy Italy. The patients’ median age was 56 years, and 52% were women. Any alteration in the sense of smell or taste was reported by 64.4% of the patients, with median score of 4. The alteration in the sense of smell or taste occurred before the onset of typical COVID-19 symptoms in 11.9% of the patients, and it was the only symptom in 3.0% of patients. Women were significantly more likely than men to report alterations in the sense of smell or taste (72.4% vs. 55.7%).

This cross-sectional survey suffers from lack of control patients — for example contemporaneous patients with respiratory symptoms who tested negative for SARS-CoV-2, or those with known infections with other respiratory viruses. Nonetheless, the Centers for Disease Control and Prevention added altered sense of smell or taste to the list of COVID-19 manifestations that would trigger priority testing. The inclusion of this symptom as a trigger for testing will likely generate data that help us define the sensitivity and specificity of this symptom when comparing COVID-19 manifestations to those of other respiratory illnesses.

Does self proning help in patients with respiratory symptoms in Covid 19?

In this observational study, oxygen saturations in patients with COVID-19 increased after self-proning for 5 minutes.

Patients with severe COVID-19 often present with profound hypoxemia. Initial recommendations for their management included early intubation, but this was not predicated on evidence. Recently, many hospitals have initiated awake or self-proning protocols early in patients’ hospital courses, in an attempt to improve oxygenation and stave off intubation. Unlike the labor-intensive and risky proning procedure in patients with acute respiratory distress syndrome (in which patients are paralyzed, sedated, and rotated onto their stomachs), with self-proning, alert patients roll onto their stomachs or sides by themselves.

In this observational study, researchers in a New York City emergency department measured the change in oxygen saturation 5 minutes after self-proning in 50 patients with hypoxia and suspected (subsequently confirmed) Covid19. Median oxygen saturation was 80% on arrival and increased to 84% after patients were placed on supplemental oxygen. After 5 minutes of proning, median oxygen saturation increased to 94%. Ultimately, 36% of patients were intubated within 72 hours and, of these, 38% (7) were intubated within the first hour.

Neurologic Symptoms and Findings Among Patients with Severe SARS-CoV-2 Infection
John C. Probasco, MD reviewing Helms J et al. N Engl J Med 2020 Apr 15

Encephalopathy, corticospinal tract signs, and frontotemporal hypoperfusion by MRI were commonly observed in the absence of detectable virus in the cerebrospinal fluid.

Researchers in France detail neurologic observations of a cohort of 58 consecutive patients admitted to two intensive care units for management of SARS-CoV-2 infection. All were positive for SARS-CoV-2 by RT-PCR assay of nasopharyngeal samples. Median age was 63 years; seven patients had a history of a neurologic disorder.

Neurologic findings were recorded on admission or when sedation and neuromuscular blockade were discontinued. Agitation was observed in 69% of patients, and 26 (65%) of 40 patients assessed met criteria for confusion. Diffuse corticospinal tract signs were present in 67% of patients. At discharge, 33% of 45 patients displayed a dysexecutive syndrome characterized by inattention, disorganization, or poorly organized movements to command.

Thirteen patients underwent brain MRI (11 with perfusion imaging) for evaluation of unexplained encephalopathy. Eight patients had leptomeningeal enhancement. Of the 11 patients with perfusion imaging, all demonstrated bilateral frontotemporal hypoperfusion. One patient had a subacute ischemic stroke. Eight patients underwent electroencephalography, which produced nonspecific findings. Of seven patients who underwent cerebrospinal fluid (CSF) analysis, none demonstrated a CSF pleocytosis and all were negative for SARS-CoV-2 in CSF by RT-PCR.

As the authors note, it is unclear to what extent these neurologic observations can be attributed directly to SARS-CoV-2 infection as opposed to encephalopathy due to critical illness, the systemic response to infection, or the effects of medications. The frequent observation of corticospinal tract signs is notable. The lack of virus or other notable findings in CSF assays could result from either absence of central nervous system infection or poor RT-PCR assay sensitivity. The asymptomatic stroke raises concern for increased stroke risk in the setting of systemic inflammation. Dysexecutive syndrome in one third of discharged patients indicates a need for close post-hospitalization follow-up. We anticipate that future studies will clarify the pathogenesis of SARS-CoV-2 neurologic syndromes and guide preventive, acute, and longitudinal treatment.

Is there a definite treatment available for COVID-19?

Since the first cases were reported in December 2019, infection with the severe acute respiratory coronavirus 2 (SARS-CoV-2) has become a worldwide pandemic. COVID-19 — the illness caused by SARS-CoV-2 — is overwhelming health care systems globally. The symptoms of SARS-CoV-2 infection vary widely, from asymptomatic disease to pneumonia and life-threatening complications, including acute respiratory distress syndrome, multisystem organ failure, and ultimately, death. Older patients and those with preexisting respiratory or cardiovascular conditions appear to be at the greatest risk for severe complications. In the absence of a proven effective therapy, current management consists of supportive care, including invasive and noninvasive oxygen support and treatment with antibiotics.8,9 In addition, many patients have received off-label or compassionate-use therapies, including antiretrovirals, antiparasitic agents, anti-inflammatory compounds, and convalescent plasma.

Remdesivir is a prodrug of a nucleotide analogue that is intracellularly metabolized to an analogue of adenosine triphosphate that inhibits viral RNA polymerases. Remdesivir has broad-spectrum activity against members of several virus families, including filoviruses (e.g., Ebola) and coronaviruses (e.g., SARS-CoV and Middle East respiratory syndrome coronavirus [MERS-CoV]) and has shown prophylactic and therapeutic efficacy in nonclinical models of these coronaviruses. In vitro testing has also shown that remdesivir has activity against SARS-CoV-2. Remdesivir appears to have a favorable clinical safety profile, as reported on the basis of experience in approximately 500 persons, including healthy volunteers and patients treated for acute Ebola virus infection

In this cohort of patients hospitalized for severe COVID-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.). Hence the compassionate use of remdimovir is being practiced even though all the studies are not completed and FDA approval not given as yet,

Vertigo: is it caused by peripheral lesions or the brain stem?

A patient is feeling unsteady or dizzy. She has difficulty in describing what she feels exactly: the room feels as if it is spinning or she is spinning while the room stands still. This is obviously illusory. She finds it difficult to maintain her balance as she has difficulty in judging the vertical dimensions of her surroundings or sometimes the horizontal dimensions. She feels unsteady and needs to hold onto a chair or table or feels that her head is spinning or that her eyes will not focus properly. In the subcontinent the word most often used to describe this feeling is “chakar” or sensation of spinning.

What is causing her to have any or all of these symptoms?

The commonest reason for vertigo is related to inflammatory lesions of the middle ear i.e. vestibular neuronitis. The common cold if severe can cause vertigo and the onset of migraine can be a cause. Travel sickness is a common cause and is usually accompanied by nausea and vomiting. Postural stability can be affected in patients with vertigo. The vestibular nuclei send signals to the vestibulospinal tract, which in turn stimulates anti-gravity muscles that maintain posture. When symptoms are less pronounced, particularly when there is pronounced nystagmus out of proportion to the severity of vertigo, think of a brainstem rather than a peripheral lesion.

Some patients may have an illusion that their body is upside down or tilted to one side. This tilt illusion, in which patients feel that they and their environment are tilted with respect to gravity, usually reflects damage to otolithic organs (utricle and saccule) or their central connections. Otolith dysfunction may also cause lateropulsion or the tendency to fall to the side of the lesion. A sudden drop to the ground without warning can occur and is called the drop attack. Drop attacks can be caused by epileptic seizures specially in older patients, or cardiogenic syncope or have a vestibular pathology.

Oscillopsia, a visual illusion of to-and-fro environmental motion and blurred vision whenever the head is in motion, is a manifestation of an impaired vestibuloocular reflex (VOR).

Impaired balance without vertigo — This is a common manifestation of acute simultaneous bilateral vestibular loss such as that occurring with aminoglycoside antibiotic toxicity. Vertigo does not occur because there is no marked vestibular asymmetry. Most patients have oscillopsia during passive head movement, as when walking or riding in a car over rough terrain. Imbalance is most marked in the dark when visual cues to position in space are not available.

How are you going to set about determining why your patient is having problems with their balancing apparatus? Take a detailed history specially of associated symptoms current or in the recent past specially related to ear, nose and throat. Ask about drugs used medicinally and for leisure. Ask about associated conditions such as diabetes, hypertension, epilepsy, past history of stroke or ischemic heart disease. Inquire about aggravating and provoking factors.

Examine the patient for nystagmus, eye movements, balance and gait. Do the DixHallpike and HINT tests, check the cranial nerves, motor and sensory systems, check the hearing clinically.

Keep in mind that vertigo comes and goes and is not a permanent symptom, Association with nystagmus and persistence of vertigo tends to occur in in stroke and brain stem lesions.

Acute onset, sustained vertigo: common diagnoses in this setting include vestibular neuritis, demyelinating disease, and a stroke in the brainstem or cerebellum.

Very brief episodes of isolated vertigo that are precipitated by predictable movements or positions of the head are often caused by benign paroxysmal peripheral vertigo (BPPV).

The Dix-Hallpike maneuver can help confirm this diagnosis. With the patient sitting, the neck is extended and turned to one side. The patient is then placed supine rapidly, so that the head hangs over the edge of the bed. The patient is kept in this position until 30 seconds have passed if no nystagmus occurs. The patient is then returned to upright, observed for another 30 seconds for nystagmus, and the maneuver is repeated with the head turned to the other side. The latency, transience, and fatigability, coupled with the typical mixed upward vertical and torsional direction, are important in diagnosing BPPV due to posterior canalithiasis.
The lack of evidence to support performance of the HINTS exam by EPs does not prove we cannot use it successfully.

Head impulse test — The head impulse test (or head thrust test) is performed by instructing the patient to keep his or her eyes on a distant target while wearing his or her usual prescription eyeglasses. The head is then turned quickly and unpredictably by the examiner, approximately 15°; the starting position should be approximately 10° from straight ahead.

The normal response is that the eyes remain on the target (figure 3). The abnormal response is that the eyes are dragged off of the target by the head turn (in one direction), followed by a saccade back to the target after the head turn; this response indicates a deficient VOR on the side of the head turn, implying a peripheral vestibular lesion (inner ear or vestibular nerve) on that side


The HINTS (Head Impulse, Nystagmus, Test of Skew) exam has been shown to accurately identify central causes of vertigo when performed by neuro-ophthalmologists on patients with acute vestibular syndrome (Stroke 2009; 40:3504). To compare the accuracy of HINTS exams performed by emergency physicians (EPs) and neurologists for identifying central causes of vertigo, researchers performed a systematic review and meta-analysis. Inclusion criteria were adult patients with acute vestibular syndrome (constant vertigo, nystagmus, ataxia) evaluated with a HINTS exam performed by any clinician, with neuroimaging as the gold standard.
In the five studies identified, overall risk of bias was moderate. In most studies, HINTS exams were performed by neurologists or neuro-ophthalmologists, with a sensitivity of 97% and specificity of 95%. Only one study included EPs, and they were fellowship-trained in vascular neurology. That study also included neurologists, and for the EPs and neurologists combined, sensitivity was 83% and specificity was 44%.

COMMENT
The aim of this study was to further confirm high accuracy of the HINTS exam when performed by neurologists and neuro-ophthalmologists. It also highlights that the little available evidence suggests EPs do not perform the exam with the same sensitivity and specificity. Despite the limited evidence, I believe EPs can learn to perform the HINTS exam accurately. The most common mistake I see is performing it on patients who don’t have vestibular syndrome. If the patient doesn’t have constant vertigo with nystagmus, they don’t have vestibular syndrome, and the HINTS exam should not be used.

(April 3, 2020 Accuracy of the HINTS Exam for Vertigo in the Hands of Emergency Physicians. Benton R. Hunter, MD reviewing Ohle R et al. Acad Emerg Med 2020 Mar 13)

MRI of the brain is indicated in selected patients when the history and examination suggest either a central cause of vertigo or a vestibular schwannoma (acoustic neuroma). CT scans are significantly less sensitive for the diagnosis of cerebellar infarction and for pathologies affecting the brainstem or vestibular nerve.

Electronystagmography and video nystagmography — ENG uses electrodes to record eye movements. VNG uses video cameras to record eye movements. These techniques record and quantify both spontaneous and induced nystagmus. Most balance disorder centers and many specialists use ENG or VNG to assess vestibular function and ocular motility.

Vestibular evoked myogenic potentials — VEMPs are a new means of assessing otolith function.

Brainstem auditory evoked potentials — BAEPs have a 90 to 95 percent sensitivity for detecting acoustic neuromas but are not used routinely in the diagnostic workup.

By now you have a fairly accurate idea as to how to work up a case of vertigo. Keep in mind that vestibular neuronitis is the commonest cause but you may pick up a brainstem or cerebellar tumor or infarct in the course of your patient examination. Do not forget demyelinating diseases.

Understanding the logic of prevention in the COVID19 disease.

The initial cases of novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) occurred in Wuhan, Hubei Province, China, in December 2019 and January 2020. The pathogen was traced to the Huanan Seafood Wholesale Market. The dynamics of method of transmission and and infection dynamics of disease have helped shape some of the measures taken to limit the spread of disease. Some of these seem to be working and some have caused catastrophes in different parts of the world. Some facts taken from a study “Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia” Published in the March 26, 2020 N Engl J Med 2020; 382:1199-1207 are given below.

Among the first 425 patients with confirmed NCIP, the median age was 59 years and 56% were male. The majority of cases (55%) with onset before January 1, 2020, were linked to the Huanan Seafood Wholesale Market, as compared with 8.6% of the subsequent cases. The mean incubation period was 5.2 days (95% confidence interval [CI], 4.1 to 7.0), with the 95th percentile of the distribution at 12.5 days. In its early stages, the epidemic doubled in size every 7.4 days. With a mean serial interval of 7.5 days (95% CI, 5.3 to 19), the basic reproductive number was estimated to be 2.2 (95% CI, 1.4 to 3.9).

There was human to human transmission, respiratory droplets were involved in the transmission, physical contact with mucosal surfaces could result in transmission of the virus to hands and then could be transmitted to any surface touched by an infected person. The transmission could take place unless controlled by hand washing and antiseptic cleaning of the surfaces, for a period of 7 days. Hence a symptomatic patient needs to be isolated for 7 days or until tests are negative for the presence of the virus. Taking into account that an asymptomatic person can also transmit the disease and the incubation period is 14 days such a person needs to be isolated for 14 days. Families can be isolated in their homes or group accommodation. It would however be advisable to isolate the elderly and vulnerable separately in a room of their own. As the virus is not transmitted by food, drink and cooking utensils meals and food can be shared. If an asymptomatic patient becomes symptomatic then they need to isolate for an additional days.

Have we had similar viruses in the past? COVID 19 was rapidly shown to be caused by a novel coronavirus that is structurally related to the virus that causes severe acute respiratory syndrome (SARS). There have been two preceding instances of emergence of coronavirus disease in the past 18 years — SARS (2002 and 2003) and Middle East respiratory syndrome (MERS) (2012 to the present) — the Covid-19 outbreak has posed critical challenges for the public health, research, and medical communities. Two pandemics of influenza occured in 1957 and 1968. Spanish flu occured in 1917.

How often have we dealt with the corona virus in the past? Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and SARS-CoV-2, have been responsible for the SARS epidemic in 2002 to 2004 and for the more recent coronavirus disease 2019 (Covid-19) pandemic. Why are these viruses infective and how do they differ from the influenza viruses? These viruses respectively, interface with the RAAS (rennin angiotensin aldosterone) through angiotensin-converting enzyme 2 (ACE2), an enzyme that physiologically counters RAAS activation also functions as a receptor for both SARS viruses. The interaction between the SARS viruses and ACE2 has been proposed as a potential factor in their infectivity. There are concerns about the use of RAAS inhibitors that may alter ACE2 and whether variation in ACE2 expression may be in part responsible for disease virulence in the ongoing Covid-19 pandemic. Indeed, some media sources and health systems have recently called for the discontinuation of ACE inhibitors and angiotensin-receptor blockers (ARBs), both prophylactically and in the context of suspected Covid-19. Is it possible that ACE2 may be beneficial rather than harmful in patients with lung injury?

Coexisting conditions, including hypertension, have consistently been reported to be more common among patients with Covid-19 who have had severe illness, been admitted to the intensive care unit, received mechanical ventilation, or died than among patients who have had mild illness. There are concerns that medical management of these coexisting conditions, including the use of RAAS inhibitors, may have contributed to the adverse health outcomes observed. However, these conditions appear to track closely with advancing age, which is emerging as the strongest predictor of Covid-19–related death.

ACE2 is a key counterregulatory enzyme that degrades angiotensin II to angiotensin-(1–7), thereby attenuating its effects on vasoconstriction, sodium retention, and fibrosis. Although angiotensin II is the primary substrate of ACE2, that enzyme also cleaves angiotensin I to angiotensin-(1–9) and participates in the hydrolysis of other peptides. In studies in humans, tissue samples from 15 organs have shown that ACE2 is expressed broadly, including in the heart and kidneys, as well as on the principal target cells for SARS-CoV-2, the lung and the alveolar cells. Of interest the role of ACE2 in the lungs appears to be relatively minimal under normal conditions but may be up-regulated in certain clinical states. ACE inhibitors in clinical use do not directly affect ACE2 activity.

SARS-CoV-2 appears not only to gain initial entry through ACE2 but also to subsequently down-regulate ACE2 expression such that the enzyme is unable to exert protective effects in organs. It has been postulated but unproven that unabated angiotensin II activity may be in part responsible for organ injury in Covid-19.

What can be done for a person who falls ill? First keep in mind that the mortality rate is low. Some people like the elderly, the immune compromised, those with other serious underlying diseases should be isolated, observed and cared for with greater intensity. Therapy currently consists of supportive care while a variety of investigational approaches are being explored. Among these are the antiviral medication lopinavir–ritonavir, interferon-1β, the RNA polymerase inhibitor remdesivir, chloroquine, and a variety of traditional Chinese medicine products. Symptomatic relief as needed has to be provided and ventilatory support needs to be available. It is the sudden demand for ICU and ventilatory support which has sent nations scrambling to impose mass isolation, social isolation and the tragic mass migration in India.

We are going to see more outbreaks of diseases related to poverty, malnutrition, emergence of new pathogens as in the wake of the economic disaster which is likely to follow this outbreak. The Covid-19 outbreak should serve as a stark reminder of the ongoing challenge of emerging and reemerging infectious pathogens and the need for constant surveillance, prompt diagnosis, and robust research to understand the basic biology of new organisms and our susceptibilities to them, as well as to develop effective countermeasures.

Paralysis in an adult man: quadriparesis/paraparesis.

A 23 year old laborer needs to be evaluated. He has been in bed for almost 3 months because his limbs are paralysed to the extent that he needs to be lifted up into a wheelchair and also when he needs a bath or a change of apparel. He needs a urinary catheter but can pass stool after being given an enema or a suppository. He has had no trauma to the neck, shoulder or head. The illness developed over 3-4 days without any headache or pain in the neck or fever. He became totally paralysed from below upwards and is now appearing to get better. On examination you find that all four limbs are involved, with marked hypertonia, grade 2-3 muscle weakness and 4-5 increased motor reflexes and up-going planter reflexes. There is no significant sensory loss. Because of the marked weakness ataxia is difficult to assess.

What is this condition?

In a regional neuroscience center in the United Kingdom, the most common cause of spastic paraparesis or quadriparesis among 585 patients was cervical spondylotic myelopathy (24 percent), followed by tumor (16 percent), multiple sclerosis (MS; 18 percent), and motor neuron disease (4 percent)

Is this transverse myelitis?

TM is a segmental spinal cord injury caused by acute inflammation usually idiopathic in origin which results in paraplegia, quadriplegia, or the Brown-Sequard syndrome. It is rapid in onset and upper motor neuron in origin. It usually occurs over a few segments and the sensory loss may be missed.TM can also occur in multiple sclerosis (MS) and can be the presenting demyelinating event. Neuromyelitis optica or Devic disease is a disorder related to MS. Remember to examine the fundi and give the reason for doing so. Connective tissue disorders can also cause TM such as systemic lupus erythematosus, mixed connective tissue disease, Sjögren’s syndrome, scleroderma, antiphospholipid antibody syndrome, ankylosing spondylitis, rheumatoid arthritis. 

Magnetic resonance imaging (MRI) of the involved section of the spinal cord shows gadolinium-enhancing signal abnormality, usually extending over one or more cord segments. The cord often appears swollen at these levels. Cerebrospinal fluid (CSF) is abnormal in half of patients, with elevated protein level (usually 100 to 120 mg/100 mL) and moderate lymphocytosis (usually <100/mm3). Glucose levels are normal. Oligoclonal bands are usually not present in isolated TM, and when present suggest a higher risk of subsequent MS

The granulomatous inflammation of sarcoidosis can affect the spinal cord and produce an acute or subacute segmental myelopathy. The lesions can be extramedullary or intramedullary, and can involve the cauda equina as well as the cord. MRI signal abnormalities are not specific; neurosarcoid lesions can appear similar to TM or can resemble a tumor. CSF evaluation usually shows elevated protein and/or pleocytosis. Hilar lymphadenopathy may suggest the diagnosis; however, serum and CSF angiotensin converting enzyme levels are neither sensitive nor specific for neurosarcoidosis. Patients with neurologic sarcoidosis are generally treated with corticosteroids and other immunomodulatory agents and can improve.

Paraneoplastic syndromes. Four of these occur are likely to be seen but are unlikely to be present in this patient. These are given below:

  • Motor neuron syndrome – a subacute, progressive, painless, and often asymmetric lower motor neuron weakness, most often associated with lymphoma
  • Acute necrotizing myelopathy – a rapidly ascending syndrome of sensory deficits, sphincter dysfunction, and flaccid or spastic paraplegia or quadriplegia
  • Subacute sensory neuronopathy – an inflammatory disorder affecting the dorsal root ganglia, producing progressive loss of sensory modalities, leading to prominent ataxia. This is most often associated with small cell lung cancer and anti-Hu antibodies.
  • Encephalomyelitis – a diffuse involvement of brain and spinal cord regions, in which cerebral manifestations frequently overshadow the myelopathy. Several syndromes are described.

Is it an acute infection?

Tuberculosis — Tuberculosis can produce a myelopathy by different mechanisms. Infection of the vertebral body leads to tuberculous spondylitis or Pott’s disease, which can lead to secondary cord compression. These patients present with back pain over the affected vertebra, low-grade fever, and weight loss, followed by a secondary compressive myelopathy. Tuberculomas within the intramedullary, intradural, and extradural space can also produce myelopathy.

Think of an acute epidural abscess specially one caused by Staph. It is a reversible cause of the paralysis. The infection can originate via contiguous spread from infections of skin and soft tissues or as a complication of spinal surgery and other invasive procedures, including indwelling epidural catheters. Other cases of epidural abscess arise from a remote site via the bloodstream. Diabetes, alcoholism, and human immunodeficiency virus (HIV) infection are risk factors.

Acute viral myelitis — Two distinct syndromes of spinal cord involvement are associated with acute viral disease. In the first, the virus targets the gray matter of the spinal cord, producing acute lower motor neuron disease. These viruses include:

●Enteroviruses, such as poliovirus, coxsackie virus, and enterovirus 71.

●Flaviviruses, such as West Nile virus and Japanese encephalitis virus.

AIDS myelopathy — HIV infection produces a vacuolar myelopathy, which is found in up to half of patients with AIDS at autopsy. However, clinical manifestations occur when the pathology is advanced, and only approximately one-fourth of patients demonstrating vacuolar myelopathy at autopsy have symptoms during life.

HTLV-I myelopathy — Human T-lymphotropic virus type I (HTLV-I) causes a progressive neurologic disease, which is called either HTLV-1-associated myelopathy (HAM) or tropical spastic paraparesis (TSP) [57,58]. This disorder is endemic in southern Japan, the Caribbean, South America, the Melanesian islands, Papua New Guinea, the Middle East, and central and southern Africa, with sero prevalence as high as 30 percent in southern Japan.

Spinal cord infarction is most frequently caused by surgical procedures and pathologies affecting the aorta but can also occur in the setting of severe systemic hypotension or cardiac arrest. Symptoms are consistent with the functional loss within the anterior spinal artery territory and include paralysis, loss of bladder function, and loss of pain and temperature sensation below the level of the lesion. Position and vibratory sensation are spared. The onset of symptoms is sudden and is frequently associated with back pain. Magnetic resonance imaging (MRI) will demonstrate a T2 signal change consistent with cord ischemia, but may be normal in the first 24 hours.

Think also of spinal a-v malformations and hematomas.

Subacute combined degeneration — Deficiency in vitamin B12 (cobalamin) leads to degeneration of the dorsal and lateral white matter of the spinal cord, producing a slowly progressive weakness, sensory ataxia, and paresthesias, and ultimately spasticity, paraplegia, and incontinence. Not all patients with neurologic abnormalities will have anemia or macrocytosis. Supplemental treatment with vitamin B12 can stop progression and will produce neurologic improvement in most patients.

Two causes of spinal cord degeneration are linked to food and are found in times of famine. Neurolathyrism is associated with prolonged consumption of the grass or chickling pea (Lathyrus sativus). Exposed persons develop a slowly developing spastic paraparesis with cramps, paresthesias, and numbness, accompanied by bladder symptoms and impotence. Konzo, a disorder characterized by acute spastic paraparesis or quadriparesis, is linked to high exposure to cyanogenic compounds in diets containing insufficiently processed bitter cassava (Manihot esculenta).

Both benign and malignant tumors can produce a myelopathy as a result of external compression or intramedullary growth.

Neoplasm. The most common syndrome is that of extradural spinal cord compression, as produced by metastases to the extradural space. Patients present with a progressive weakness below the level of the lesion with accompanying sensory loss and bladder dysfunction. Diagnostic evaluation (with gadolinium-enhanced spinal magnetic resonance imaging [MRI]) must proceed promptly when this diagnosis is considered. Intramedullary spinal cord tumors are typically primary central nervous system tumors (ependymoma, astrocytoma); metastases are less likely. These produce a progressive myelopathy, often with central cord features. MRI with gadolinium will show the tumor. Myelopathy can also occur as a complication of radiation therapy.

Is this Friedreich’s ataxia?

The neuropathologic changes in Friedreich ataxia include degeneration of the posterior columns and the spinocerebellar tracts of the spinal cord and loss of the larger sensory cells of the dorsal root ganglia. These findings correspond to the clinical manifestations of progressive ataxia of all four limbs and gait, weakness, absent reflexes with extensor plantar responses, loss of position and vibration sense, and sparing of pain and temperature. Cardiomyopathy and diabetes mellitus are part of the syndrome. Patients with late-onset disease are more likely to have retained reflexes, spasticity, and no cardiomyopathy. MRI may show atrophy of the cervical cord. Disease severity and rate of progression are highly variable. This condition is unlikely in this patient as he came in with muscle weakness not ataxia, he has no dysphasia, dysphagia, loss of sense of position and vibration. His reflexes are exaggerated and muscle tone increased. In Friedreich’s ataxia in very late onset cases there may rarely be spasticity. Check out genetic evidence of frataxin repeats (GAA), frataxin level, vitamin E level in serum (should be normal) and no cerebellar atrophy on the MRI of the brain. There is no cure.

This is an extensive subject. I have not touched on traumatic myelopathy but i have given you plenty of thought for reading up for an exam and answering some of the common questions likely to be asked.

Purpose of assessment: how to understand and plan your answer in an interactive session. Thyroiditis and Celiac Disease.

Part of an assessment aka clinical examination in a postgraduate setting, is a series of scenarios or clinical material which a candidate is asked to read and assess, What is the purpose of this form of assessment?

About the scenario: do you understand the information that is given you? Can you make a working diagnosis? Can you try to prove your diagnosis? Can you make the patient comfortable, recognize and treat complications and life threatening situations, can you restore normal or near normal functions, and follow up the patient’s functions? Obviously in the short time allotted you will be asked some of these questions but these are the questions you should prepare.

Sample 1. A 32 year old man from the Northern Areas of Pakistan. He had been unwell for 2 months. The 2 main problems were irregular low grade fever and pain in the front of the neck radiating to the jaw and temporal regions. His local caregiver has given him 3 courses of different antibiotics with the intention of treating a sore throat/pharyngitis but he has not improved. His fever is 101 degree F, with a regular pulse of 110/min, he has fine tremors in both hands and feels nervous and jittery. his appetite is good but he has lost 3 kg of weight. His ENT examination is unremarkable and the front of the neck is tender, and there is a firm palpable non-cystic small mass.

What will the examiner ask you?

  • What is the likely diagnosis or problem?
  • What disease is he suffering from?
  • Why have you reached this conclusion?
  • What is the relevant information in this scenario?
  • What is the organ or system involved?

All these are designed to see if you understood the information in the scenario and interpreted it intelligently. Answers given were as below;

  • Temporal arteritis. Wrong. You have been told that the pain begins in the front of the neck and then radiates. In temporal arteritis or giant cell arteritis temporal headaches are pretty severe and the tenderness is in the temporal regions. It is also known as Horton’s disease, and major manifestations on the basis of which it is diagnosed are new headaches, abrupt onset of visual disturbances, especially transient monocular visual loss, jaw claudication, unexplained fever, anemia, or other constitutional symptoms and signs. Labs will show high erythrocyte sedimentation rate (ESR) and/or high serum C-reactive protein (CRP). None of these are mentioned in the scenario.
  • Thyroiditis: subacute is the right answer. What else is tender other than the thyroid? It is painful and tender and there is fever hence it is inflamed so it is thyroiditis as the gland is inflamed, it has been there for 2 months so not acute and not yet quite chronic and the symptoms are muted too. There is no hint of jaw claudication in the scenario and no evidence of AF. Subacute thyroiditis is fundamentally a clinical diagnosis. In most patients, clinical manifestations (the presence of neck pain, often radiating upward to the jaw; marked thyroid tenderness; and a diffuse goiter) are sufficient to establish the diagnosis. Symptoms and signs of hyperthyroidism may or may not be present, but the serum TSH is usually suppressed (typically <0.1 mU/L) and free T4 and T3 concentrations elevated, particularly in the early stages of the illness.
  • You will be asked what specific tests you will do to further your diagnosis: prove absence of bacteria, blood culture, throat swab culture etc; C-reactive protein and ESR to prove ongoing active inflammation: check the thyroid status usually mild hyperthyroidism with low TSH. antithyroid antibodies will be absent, radioiodine uptake will be low. Thyroid crisis is unlikely to occur. Doppler ultrasound of the neck will show reduced thyroid blood flow.
  • How will you treat or manage this case and what is the objective of your management?The objective is to make the patient comfortable, reduce the inflammation and monitor thyroid function and restore it to normal. The disease is self limiting and will subside in a few weeks to months. No antibiotics are required, a full standard dose of aspirin is effective or ibuprofen or naproxen will relieve the pain and fever; no need to treat the tremors as they will settle by themselves. If the patient does not respond in a few days use an adequate dose of steroids.
  • Differential diagnosis: rarely, fine-needle aspiration biopsy, typically under ultrasound guidance, is necessary to distinguish infection (eg, abscess), hemorrhage, thyroid cancer, or lymphoma from subacute thyroiditis. However, considering the possibility of the presence of a thyroid abscess is important in all cases of subacute thyroiditis. Occasional patients with either chronic autoimmune thyroiditis (Hashimoto’s thyroiditis) or Graves’ hyperthyroidism have neck pain and tenderness. However, the pain in both conditions is much less severe than in subacute thyroiditis, while thyroid dysfunction should be much more severe. In Graves’ hyperthyroidism, radioactive iodine uptake is high, not low. Painless (silent) and postpartum thyroiditis may cause similar changes in thyroid function and are associated with low radioiodine uptake, but thyroid gland or neck tenderness is not present.
  • Thyroid status usually returns to normal i.e euthyroid and therapy for hypothyroidism is not needed because symptoms, are not pronounced but if the hypothyroidism is more pronounced (TSH >10 mU/L) or associated with more than mild symptoms, the patient should be treated with 50 to 100 mcg of T4 (levothyroxine) for six to eight weeks (with a goal TSH in the normal range). The T4 should then be discontinued, and the patient reevaluated in four to six weeks to be sure that the hypothyroidism is not permanent.

When you are preparing for the exam this is the information you need about subacute thyroiditis. Organise it in your own mind. Remember that diagnosis depends on some or one salient point, this may be clinical or a lab investigation or a series of lab investigations. Understand and remember these. In the examination it is often obvious that the candidate is thinking of these points for the first time. This is fatal. Treatment consists of reducing distress, pain and discomfort. This is very important and not just an adjunct to the curative treatment. The curative or corrective treatment is an attempt to restore function. You may need to supply the missing hormone, electrolyte, vitamin or enzyme etc or if it is in excess then to block it with drugs or other therapy. You have to anticipate and recognize complications and then rehabilitate the patient.

Remember to read up these points. Finally read up research and controversies, recent advances and remember the name of a current or recently published trial.

If a scenario was being written about Adult Coeliac Disease what would the assessor include?

  • For acute disease: some form of diarrhoea (not bloody or with mucus), recent onset but with a history of recurrence over months, weight loss, may not always be related to intake of wheat as adult will have been on wheat all their lives, evidence of malabsorption such as anemia (iron deficiency, folate and vitamin B 12 deficiency, vitamin D deficiency). What tests you will be expected to do to prove that it is coeliac disease: intestinal biopsy for villous atrophy and some tests for gluten enteropathy such as autoantibodies; anti-endomysial antibody (EMA-IgA), anti-tissue transglutaminase antibodies (tTG) (tTG-IgA, tTG-IgG), or antibodies targeting gliadin, antibody to native gliadin: anti-gliadin antibody (AGA-IgA, AGA-IgG), antibodies against synthetic deamidated gliadin peptides: Deamidated gliadin peptide (DGP)-IgA, DGP-IgG. Anti-gliadin antibodies are unreliable as there are too many false positives. Undetectable IgA levels but not partial immunoglobulin A deficiency (low but detectable serum IgA) decreases the sensitivity of TTG-IgA.
  • Points in the scenario may give probability of disease: low probability; absence of suggestive signs or symptoms of malabsorption such as significant chronic diarrhea/steatorrhea or weight loss,, absence of family history of celiac disease, Chinese, Japanese, or Sub-Saharan African descent. High probability is likely if there are symptoms suggestive of intestinal coeliac disease or evidence of extra-intestinal diseases; malabsorption or nutrient deficiency plus risk factors such as first and second degree relative with confirmed celiac disease Type 1 diabetes, autoimmune thyroiditis, Down and Turner syndromes, pulmonary hemosiderosis (moderate risk).
  • What is the value of doing HLA testing? Only a 12% negative value if the usual HLA typing is absent. If HLA DQ2/DQ8 is negative, celiac disease is excluded.
  • These need to be excluded: irritable bowel syndrome, small intestinal bacterial overgrowth, lactose intolerance, chronic pancreatitis, microscopic colitis, and inflammatory bowel disease. Celiac disease can be differentiated from these by serologic evaluation and small bowel biopsy.
  • Why follow up coeliac disease? To correct the nutrient deficiency and look out for malignancy.

Whenever you are revising for an interactive assessment pick out the salient points and not just remember them but understand them.