Respiratory system notes – Week 5

Notes on Goodpasture syndrome, Influenza, Croup, Epiglottitis, Tracheitis, Pertussis

Goodpasture syndrome
(anti-GBM antibody disease – against lungs and kidneys)

A 36-year-old man presents to his primary care physician complaining of a 1-w history of progressively worsening fatigue, anorexia, cough, and dark urine. Over the past 2 d he has become alarmed when he noticed bloody flecks in his sputum. He has been having intermittent shortness of breath. He has no prior family history of renal disease and has smoked for 18 y.

(This is not my work, info is cut and pasted from various sources)

  • Discuss the autoantibody response in Goodpasture syndrome

(From Up To Date)

Intro: Anti-GBM antibody disease is a disorder in which circulating antibodies are directed against an antigen intrinsic to the glomerular basement membrane (GBM), thereby resulting in acute or rapidly progressive glomerulonephritis that is typically associated with crescent formation. The term Goodpasture’s disease is often reserved for those patients with glomerulonephritis, pulmonary hemorrhage, and anti-GBM antibodies.

Response: In the disease, there is short-lived production of circulating autoantibodies, which are directed against an antigen intrinsic to the glomerular basement membrane (GBM), in response to an unknown inciting stimulus. The development of anti-GBM antibodies may precede the onset of clinical signs and symptoms by many months. The principal target for the anti-GBM antibodies (which are typically immunoglobulin G (IgG) 1 and 3 but sometimes IgA or IgM) is the NC1 domain of the alpha-3 chain of type IV collagen (alpha-3(IV) chain), one of six genetically distinct gene products found in basement membrane collagen.

  • Discuss the complement cascade that results in tissue injury

Binding of anti-GBM autoantibodies to the GBM leads to autoimmune damage characterized by strong activation of the complement (evidenced by deposits of C3), infiltration of leukocytes into the inflamed tissue, and proteinuria. All this leads to the deterioration and loss of renal function. The research shows that the complement system plays a role in renal injury due to Goodpasture’s syndrome by the proinflammatory effect of classical pathway activated C5a and/or cell lysis effect of C5b-9.

  • Why are the lung and kidney, and not other anatomic sites, susceptible to the autoantibodies?

Becuase point of filtration it is vulnerable? – The anti-GBM antibodies attack the alveoli and glomeruli basement membranes.These antibodies bind their reactive epitopes to the basement membranes and activate the complement cascade, leading to the death of tagged cells. T cells are also implicated. It is generally considered a type II hypersensitivity reaction.

  • Discuss the risk factors associated with Goodpasture syndrome

– Exposure to certain chemicals, such as hydrocarbon solvents and the weed killer paraquat
– Exposure to metallic dust
– Use of certain drugs, such as cocaine
– Tobacco smoking
– Viral infections

There is increasing evidence that genetic factors affect the susceptibility to anti-GBM antibody disease. Patients with HLA-DR15 and DR4 appear to be at increased risk, while those with DR1 and DR7 are at lesser risk [52]. The association with DR15 has been confirmed in Chinese [53] and Japanese patients [54]. More specific molecular analysis of DR beta chains has found that a particular six amino acid motif common to DRw15 and DR4 may confer disease susceptibility [55]. This motif is not seen in DR1 and is uncommon in blacks, who also have a lower incidence of anti-GBM antibody disease. One experimental study suggests that the protective effect of DR1 is associated with a shift in the phenotype of alpha3(IV) chain135-145-specific CD4+ T cells from a proinflammatory to a tolerogenic phenotype [56].

  • Discuss the concept of unmasking hidden epitopes

Goodpasture epitopes in the native autoantigen are cryptic (sequestered) within the NC1 hexamers of the α3α4α5(IV) collagen network. BUT – The biochemical mechanism for crypticity and exposure for autoantibody binding is not known.

One study reported that crypticity is a feature of the quaternary structure of two distinct subsets of α3α4α5(IV) NC1 hexamers: autoantibody-reactive M-hexamers containing only monomer subunits and autoantibody-impenetrable D-hexamers composed of both dimer and monomer subunits.

Although α3(IV) collagen is present in the thymus and available for induction of T cell tolerance (26), autoreactive T cells still escape elimination and circulate (27).

The crypticity of the GP epitopes (the part of an antigen molecule to which an antibody attaches itself) in tissue basement membranes makes it unlikely, however, that autoreactive T cells in the peripheral immune system will expand without an external precipitating event.

As mentioned above –  pathogenic factors include exposure to solvents (28, 29), inhaled smoke (30), or endogenous reactive oxygen species (15). Decondensation of α3α4α5 hexamers by non-immune mechanisms in a host expressing immune susceptibility genes (31, 32) might activate residual auto-reactive helper T cells that expand the B cell repertoire against GP epitopes encoded by the α3(IV) collagen chain (5). One study suggests that GP antibodies could further damage the GBM by accelerating epitope exposure.

Goodpasture antibodies only breach the quaternary structure of M-hexamers, unmasking the cryptic epitopes, whereas D-hexamers are resistant to autoantibodies under native conditions.

The epitopes of D-hexamers are structurally sequestered by dimer reinforcement of the quaternary complex, which represents a new molecular solution for conferring immunologic privilege to a potential autoantigen. Dissociation of non-reinforced M-α3α4α5(IV) hexamers by Goodpasture antibodies is a novel mechanism whereby pathogenic autoantibodies gain access to cryptic B cell epitopes.

These findings provide fundamental new insights into immune privilege and the molecular mechanisms underlying the pathogenesis of human autoimmune Goodpasture disease.

  • Discuss the symptoms of Goodpasture syndrome

The antiglomerular basement membrane (GBM) antibodies primarily attack the kidneys and lungs:

Generalized symptoms –

– malaise, weight loss, fatigue, fever, and chills are also common, as are joint aches and pains.[4]

Lung symptoms usually antedate kidney symptoms and usually include: coughing up blood, chest pain (in less than 50% of cases overall), cough, and shortness of breath.[5]

Kidney symptoms usually include blood in the urine, protein in the urine, unexplained swelling of limbs or face, high amounts of urea in the blood, and high blood pressure.[4]

  • How is Goodpasture syndrome diagnosed?

The diagnosis of anti-GBM antibody disease requires demonstration of anti-GBM antibodies either in the serum or the kidney. Renal biopsy should be performed, unless there is a contraindication, because the accuracy of serologic assays is variable. In addition, renal biopsy provides important information regarding the activity and chronicity of renal involvement that may help guide therapy.

The diagnosis of GPS is often difficult, as numerous other diseases can cause the various manifestations of the condition.

On top of the anti-GBM antibodies implicated in the disease, about one in three of those affected also has cytoplasmic antineutrophilic antibodies in their bloodstream, which often predates the anti-GBM antibodies by about a few months or even years.[7] The later the disease is diagnosed, the worse the outcome is for the affected person.[6]

  • Discuss the differential diagnosis of Goodpasture syndrome

A 36-year-old man presents to his primary care physician complaining of a 1-w history of progressively worsening fatigue, anorexia, cough, and dark urine. Over the past two days has become alarmed when he noticed bloody flecks in his sputum. He has been having intermittent shortness of breath. He has no prior family history of renal disease and has smoked for 18 y.

Acute Glomerulonephritis

Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome)

Community-Acquired Pneumonia (CAP)

Granulomatosis with Polyangiitis (Wegener Granulomatosis)

Pneumocystis jiroveci Pneumonia (PJP)

Respiratory Failure

Rheumatoid Arthritis

Undifferentiated Connective-Tissue Disease

  • Discuss the treatment options for Goodpasture syndrome

The treatment of choice in anti-GBM antibody disease is intensive plasmapheresis combined with prednisone and cyclophosphamide [1,3-8].

Plasmapheresis removes circulating anti-GBM antibodies and other mediators of inflammation, while the immunosuppressive agents minimize new antibody formation.

These drugs decrease the immune system’s production of Goodpasture syndrome antibodies. In some cases, intravenous corticosteroids may be needed to control bleeding in the lungs.

  • Discuss the prognosis for Goodpasture syndrome

In view of the self-limited nature of anti-GBM antibody disease, patients who survive the first year with intact renal function generally do well.

As for renal, patient survival correlates closely with the degree of renal impairment at presentation [3,37]. Patients with moderate to severe disease who do not require dialysis upon presentation generally respond to therapy, with recovery being maintained during long-term follow-up.

By comparison, few who require immediate dialysis escape the need for maintenance dialysis. 

Relapses are uncommon (around two percent in one center’s experience), but data are not sufficient to determine reliably how often this occurs [3,39-42]. Clinical relapses are more common in patients who are also ANCA-positive, in whom it is the vasculitis and not the anti-GBM antibody disease that is reactivated [25].

There may be a higher rate of recurrence in the patient who is a smoker or has exposure to hydrocarbon in his occupation. It is recommended that all patients with anti-GBM disease refrain from smoking and, when relevant, change their environment.

The outcome in patients with recurrent disease, whether ANCA positive or negative, is typically superior to that in the initial presentation of anti-GBM antibody disease [43].

Influenza

A 45-year-old man became abruptly ill with fever, headache, malaise, anorexia, and photophobia less than 2 days after having been exposed to co-workers who were coughing. In the physician’s office he had a T of 103oF associated with clear nasal discharge and cough. Because influenza was present in the patient’s geographic area, the diagnosis of influenza was made.

  • Describe the role of the hemaglutin glycoprotein and the neuraminidase glycoprotein in infection by the influenza virus

Influenza hemagglutinin (HA) or haemagglutinin (British English) is a glycoprotein found on the surface of influenza viruses. It is responsible for binding the virus to cells with sialic acid on the membranes, such as cells in the upper respiratory tract or erythrocytes.[1] It is also responsible for the fusion of the viral envelope with the endosome membrane, after the pH has been reduced. The name “hemagglutinin” comes from the protein’s ability to cause red blood cells (erythrocytes) to clump together (“agglutinate”) in vitro.[2]

Viral neuraminidase is a type of neuraminidase found on the surface of influenza viruses that enables the virus to be released from the host cell. Neuraminidases are enzymes that cleave sialic acid groups from glycoproteins and are required for influenza virus replication.

Research has focused on understanding the structural basis of the interaction of the two major surface glycoproteins of influenza A virus with their common ligand/substrate: carbohydrate chains terminating in sialic acid.

The specificity of virus attachment to target cells is mediated by hemagglutinin, which acquires characteristic changes in its receptor-binding site to switch its host from avian species to humans.

Anti-influenza drugs mimic the natural sialic acid substrate of the virus neuraminidase enzyme but utilize the much tighter binding of the drugs for efficacy.

Resistance to one of the two main antiviral drugs is differentially acquired by the two distinct subsets of neuraminidase as a consequence of structural differences in the enzyme active site between the two phylogenetic groups.

  • Distinguish between antigenic drift and antigenic shift

Influenza viruses are constantly changing. They can change in two different ways.

One way they change is called “antigenic drift. These are small changes in the genes of influenza viruses that happen continually over time as the virus replicates. These small genetic changes usually produce viruses that are pretty closely related to one another, which can be illustrated by their location close together on a phylogenetic tree. Viruses that are closely related to each other usually share the same antigenic properties and an immune system exposed to an similar virus will usually recognize it and respond. (This is sometimes called cross-protection.)

This process works as follows: a person infected with a particular flu virus develops antibody against that virus. As antigenic changes accumulate, the antibodies created against the older viruses no longer recognize the “newer” virus, and the person can get sick again. Genetic changes that result in a virus with different antigenic properties is the main reason why people can get the flu more than one time. This is also why the flu vaccine composition must be reviewed each year, and updated as needed to keep up with evolving viruses.

The other type of change is called “antigenic shift.” Antigenic shift is an abrupt, major change in the influenza A viruses, resulting in new hemagglutinin and/or new hemagglutinin and neuraminidase proteins in influenza viruses that infect humans. Shift results in a new influenza A subtype or a virus with a hemagglutinin or a hemagglutinin and neuraminidase combination that has emerged from an animal population that is so different from the same subtype in humans that most people do not have immunity to the new (e.g. novel) virus. Such a “shift” occurred in the spring of 2009, when an H1N1 virus with a new combination of genes emerged to infect people and quickly spread, causing a pandemic. When shift happens, most people have little or no protection against the new virus.

While influenza viruses are changing by antigenic drift all the time, antigenic shift happens only occasionally. Type A viruses undergo both kinds of changes; influenza type B viruses change only by the more gradual process of antigenic drift.

  • Describe how influenza virus infection is transmitted from person-to-person by virus-containing respiratory secretions

Respiratory viruses spread via three different transmission routes:

1. contact (direct or indirect),
Contact transmission refers to direct virus transfer from an infected person to a susceptible individual (e.g. via contaminated hands) or indirect virus transfer via intermediate objects (fomites).

2. droplet and

3. aerosol transmission (Table 1) [2,3].
Transmission of virus through the air can occur via droplets or aerosols.

The commonly accepted cut-off size between the large droplets and small aerosols is 5 μm, although this varies considerably between studies, ranging up to 12 μm [4–8]. Droplets generated during coughing, sneezing or talking do not remain suspended in air and travel less than 1 m before settling on the mucosa of close contacts or environmental surfaces. Aerosols have a slow settling velocity, thus they remain suspended in the air longer and can travel further [5,9,10].

  • Describe how influenza virus damages the bronchial epithelium causing depressed mucociliary clearance, which may set the stage for secondary bacterial infection

Influenza virus infections increase susceptibility to secondary bacterial infections, such as pneumococcal pneumonia, resulting in increased morbidity and mortality.

Influenza-induced tissue damage is hypothesized to increase susceptibility to Streptococcus pneumoniae infection by increasing adherence to the respiratory epithelium.

In once case:

It shows that an influenza infection increases the number of pneumococci within the trachea by inhibiting tracheal mucociliary velocity and clearance of pneumococci. This research will lead to a better understanding of how to prevent and/or treat secondary bacterial pneumonia after an influenza infection.

  • Review the main clinical manifestations of the influenza syndrome

  • Describe the three pneumonic syndromes: primary influenza viral pneumonia; secondary bacterial pneumonia; and mixed viral and bacterial pneumonia.

Primary viral pneumonia is recognized as the most severe pulmonary manifestation of influenza.

Primary influenza pneumonia, caused by direct infection of the lung parenchyma by the influenza virus, is the least common of the pneumonic complications and has a mortality rate of 10–20%. Presentation is often abrupt and dramatic, progressing within 24 h to severe pneumonia with respiratory failure and shock. Non-fatal cases recover 5–16 days after pneumonia onset, but residual lung damage is frequent.

Secondary bacterial pneumonia, with a mortality rate of approximately 7%, may be easier to differentiate from combined viral–bacterial pneumonia, as patients typically improve as expected and then deteriorate with symptoms or signs suggestive of bacterial pneumonia, including chills, rigors, increased productive cough, pleuritic chest pain, and dyspnea.1

Combined viral–bacterial pneumonia is at least three times more common than viral pneumonia, from which it is clinically indistinguishable, and presents a mortality of about 10%. Its diagnosis requires isolation of pathogenic bacteria.

  • Describe detection of viral RNA by nucleic acid amplification testing (NAAT), the test of choice for hospitalized patients

Whereas antibody positivity cannot occur until the immune system has had days or weeks to develop a sizable subpopulation of antibodies specific to the pathogen, a NAT can detect a pathogen as soon as it is present.

sooo..a nucleic acid test (NAT) or nucleic acid amplification test (NAAT) is a molecular technique used to detect a particular pathogen (virus or bacterium) in a specimen of blood or other tissue or body fluid.

It does so by detecting and amplifying the RNA or DNA of the pathogen, – making extra copies of its nucleic acids. This type of medical test was developed to shorten the window period, a time between when a patient has been infected and when they show up as positive by antibody tests such as ELISA.

  • Summarize various vaccines available for influenza

  • Describe inhaled zanamivir and oral oseltamivir for chemoprophylaxis of influenza A and B

inhaled zanamivir (trade name Relenza®), and intravenous peramivir (trade name Rapivab®). are chemically related antiviral medications known as neuraminidase inhibitors that have activity against both influenza A and B viruses. Generic oseltamivir was approved by the FDA in August 2016 and became available in December of 2016.

Antiviral resistance to oseltamivir, zanamivir, and peramivir among circulating influenza viruses is currently low, but this can change. Also, antiviral resistance can emerge during or after treatment in some patients (e.g., immunocompromised).

Interesting: CDC – Weekly U.S. Influenza Surveillance Report
https://www.cdc.gov/flu/weekly/index.htm

  • Describe the use of zanamivir and oseltamivir for treatment of patients with proven or suspected influenza

double-dose oseltamivir treatment (two times a day at 150 mg each) has been recommended for the treatment of A/H5N1 avian influenza infection considering the decreased oral absorption rate and the safety data for high-dose administration.

  • Understand that because widespread antiviral resistance has developed to rimantadine and amantadine, they are no longer recommended to treat influenza

Jan. 20, 2006 — Most cases of influenza are influenza A (H3N2), and 90% have resistance mutations for amantadine and rimantadine, according to the results of the US Centers for Disease Control and Prevention (CDC) surveillance reported in the January 17 issue of MMWR Dispatch.

However, amantadine may continue to be used to treat symptoms of Parkinson disease.

Croup, Epiglottitis, Tracheitis

A 2 ½ year old boy is brought to the emergency room by his parents just before midnight. He has developed sudden onset of a seal-like barking cough, accompanied by clear nasal discharge (rhinitis). His parents became alarmed after he developed stridor (a harsh high-pitched upper respiratory sound), which persists during the trip to the hospital. On exam, he has a seal-like barky cough and inspiratory stridor at rest, which becomes worse if he is agitated. The clinical impression is croup.

  • Differentiate among the 4 main acute inflammatory upper airway obstructions (croup, epiglotittis, laryngitis, and bacterial tracheitis)

Croup is a common respiratory problem in young children. It tends to occur in the fall and winter. Its main symptom is a harsh, barking cough. Croup causes swelling and narrowing in the voice box, windpipe, and breathing tubes that lead to the lungs. This can make it hard for your child to breathe. STRIDOR ON INSPIRATION.

Epiglottitis is inflammation of the epiglottis—the flap at the base of the tongue that keeps food from going into the trachea (windpipe). Symptoms are usually rapid in onset and include trouble swallowing which can result in drooling, changes to the voice, fever, and an increased breathing rate.

Epiglottitis is a cellulitis of the supraglottis with the potential to cause airway compromise, and should be treated as a surgical emergency until the airway is examined and secured. Pertinent diagnostic criteria include the classic ‘tripod’ position of the patient, drooling, high fever, and a toxic appearance.

Laryngitis occurs when your voice box or vocal cords become inflamed from overuse, irritation, or infection. Laryngitis can be acute (short-term), lasting less than three weeks. Or it can be chronic (long-term), lasting more than three weeks. Many conditions can cause the inflammation that results in laryngitis.

Bacterial tracheitis is an infection of the windpipe (trachea) caused by bacteria. Bacterial tracheitis is rare and can affect children of any age. The bacteria Staphylococcus aureus and streptococci are most frequently the cause.

  • Describe the dramatic increase in airway resistance associated with minor reductions in cross-sectional area of an infant’s or child’s already narrow airway

Airway resistance is the pressure difference between mouth and alveoli, divided by airflow. The chief sites of airway resistance are the medium-sized bronchi. Airway resistance is increased at low lung volumes due to reduced airway diameter and at high gas-flow rates due to turbulent flow (e.g., during forced expiration). Diseases in which airway narrowing occurs, such as chronic obstructive pulmonary disease and asthma, increase airway resistance.

Increased airway resistance can result in the following:

• Increased work of breathing in spontaneously breathing patients

• Increased time required for inflation and deflation of the lungs, which contributes to air trapping, high airway pressures, and hypoxemia in ventilated patients.

  • Describe the epidemiology of epiglottitis, and why there has been a drastic decline in cases caused by H. influenza

I’ll use the example of the UK:

Paediatric cases of epiglottitis declined markedly in England following the introduction of safe effective immunization against Haemophilus influenzae type b (Hib). And with a recently resurgence in Hib infections, a corresponding rise in the number of presentations of clinical epiglottitis in children was observed, although numbers were still well below those reported prior to vaccine availability. Before widespread Haemophilus influenzae type b (Hib) vaccination, H influenzae caused almost all pediatric cases of epiglottitis.

  • Discuss other bacterial causes of epiglottitis
  • Streptococcus pneumoniae (pneumococcus), another bacterium that can cause meningitis, pneumonia, ear infections and blood infection (septicemia)
  • Streptococcus A, B and C, a group of bacteria that also can cause diseases ranging from strep throat to blood infections
  • Describe the clinical manifestations of croup, and prodromal symptoms before the development of barking cough and stridor

Coryza is a term that describes the inflammation of the mucous membrane in the nasal cavity which results to nasal congestion, loss of smell and others.

  • Describe the clinical manifestations of epiglottitis

  • Briefly describe laryngitis and spasmodic croup

  • Review the differential diagnosis of upper airway obstructive disorders

  • Describe complications of croup

  • Describe treatment of croup with nebulized racemic epinephrine and oral dexamethasone

As an overview: A single dose of dexamethasone (0.15 to 0.60 mg per kg usually given orally) is recommended in all patients with croup, including those with mild disease. Nebulized epinephrine is an accepted treatment in patients with moderate to severe croup.

  • Discuss emergency treatment of epiglottitis, including insertion of an artificial airway, and intravenous administration of a third-generation cephalosporin

Obstruction in acute epiglottitis can be reduced by using dexamethasone therapy or budesonide aerosols to treat pharyngeal edema. In addition, research suggests that length of stay in the intensive care unit (ICU) and in the hospital overall can be reduced with corticosteroid use

Antibiotic therapy should begin after blood and epiglottic cultures have been obtained. Antipyretic agents may also be necessary. Racemic epinephrine, corticosteroids, and beta-agonists have not been proven to be helpful in epiglottitis. In addition, corticosteroid usage remains controversial, as anecdotal reports in the past had supported its use.

Third-generation cephalosporins have been available for the past 5 years. The continued increase in resistance of bacteria to older antimicrobial agents and the safety profile of a number of the third-generation agents have established situations in which these compounds are useful. Upper respiratory infections such as epiglottitis, lower respiratory tract infections due to Enterobacteriaceae are examples of illnesses in which third-generation cephalosporins would be preferred to older drug programmes.

  • Discuss prognosis

No long-term monitoring is needed after resolution of the acute episode. Follow up should be obtained with an otolaryngologist upon discharge from the hospital to ensure no sequelae from the resultant intubation. If necessary, follow up with the infectious disease physicians treating the patient may be added. It is recommended that immunization be obtained if not done previously. If previously vaccinated, titers with Haemophilus influenzae type B (Hib) may be checked, as vaccine failures have been reported.

Patient Instructions
Patient should be vaccinated with Haemophilus influenzae type B (Hib) conjugated vaccine if not previously done so.

  • Distinguish between clinical manifestations of bacterial tracheitis and epiglottitis

  • Describe treatment of bacterial tracheitis with vancomycin or clindamycin, and a third-generation cephalosporin

Antibiotic regimens have traditionally included a third-generation cephalosporin (eg, cefotaxime, ceftriaxone) and a penicillinase-resistant penicillin (eg, oxacillin, nafcillin). Recently, clindamycin (40 mg/kg/d intravenously [IV], divided every 8 h) is used instead of penicillinase-resistant penicillin against community acquired–methicillin-resistant S aureus (CA-MRSA) in places where resistance rates of CA-MRSA to clindamycin is low.

Vancomycin (45 mg/kg/d IV, divided every 8 h), with or without clindamycin, should be started in patients who appear toxic or have multiorgan involvement or if MRSA is prevalent in the community.

  • Describe complications and prognosis of bacterial tracheitis

The toxic shock syndrome, septic shock, pulmonary oedema, and the acute respiratory distress syndrome (ARDS) were recognised in four children with bacterial tracheitis.

Pertussis

A 13-month-old female infant presents with spasmodic cough, and cyanosis around her lips and fingers when coughing. She also vomits following bouts of coughing. Her parents report that she has had a cold for approximately 3 weeks, and that the infant’s appetite has decreased. The infant’s mother informs the physician that she has been coughing for about 6 weeks. The infant’s immunizations are not complete.

  • Review the epidemiology of pertussis

  • Discuss the dramatic impact of vaccinating against pertussis.

– Pertussis vaccination is effective in reducing the severity of illness.

– the vaccine itself is effective at reducing overall transmission,

– routine vaccination alone would be insufficient for elimination of the disease.

– the core transmission group is schoolchildren. Therefore, efforts aimed at curtailing transmission in the population at large, and especially in vulnerable infants, are more likely to succeed if targeted at schoolchildren, rather than adults.

  • Discuss the problem of rapidly waning protection following acellular pertussis vaccines (both DTaP and Tdap)

Because of the effectiveness of diphtheria-tetanus-acellular pertussis abstract
(DTaP) vaccine wanes substantially after the fifth dose at ages 4 to 6 years, there is a growing cohort of adolescents who rely on tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) for protection against pertussis. Yet despite high Tdap vaccine coverage among adolescents, California experienced large pertussis outbreaks in 2010 and 2014.

CONCLUSIONS: Routine Tdap did not prevent pertussis outbreaks. Among adolescents who have only received DTaP vaccines in childhood, Tdap provided moderate protection against pertussis during the first year and then waned rapidly so that little protection remained 2-3 years after vaccination.

  • Discuss possible reasons for the resurgence of pertussis

Whooping cough has made an astonishing comeback, with 2012 seeing nearly 50,000 infections in the U.S. (the most since 1955), and a death rate in infants three times that of the rest of the population. The dramatic resurgence has puzzled public health officials, who have pointed to the waning effectiveness of the current vaccine and growing anti-vaccine sentiment as the most likely culprits.

This study said – The dramatic resurgence of whooping cough is due, in large part, to vaccinated people who are infectious but who do not display the symptoms, suggests a new study.

Their research points to a different, but related, source of the outbreak — vaccinated people who are infectious but who do not display the symptoms of whooping cough, suggesting that the number of people transmitting without symptoms may be many times greater than those transmitting with symptoms.

In the 1950s, highly successful vaccines based on inactivated pertussis cells (the bacteria that causes whooping cough) drove infection rates in the U.S. below one case per 100,000 people. But adverse side effects of those vaccines led to the development and introduction in the 1990s of acellular pertussis vaccines, which use just a handful of the bacteria’s proteins and bypass most of the side effects. (Currently given to children as part of the Tdap vaccine.)

The problem is, the newer vaccines might not block transmission.

  • Discuss the pathogenesis of pertussis, which colonizes only ciliated epithelium

During the course of infection, Bordetella pertussis adheres to the ciliated epithelium, invades alveolar macrophages, multiplies rapidly on the mucous membrane and expresses various virulence factors that help colonize the upper respiratory tract by specific adhesion to the ciliated cells.

These factors include cell surface proteins and several extracellular toxins that inhibit host defenses and induce damage to host tissues.

The expression of the virulence factors in Bordetella pertussis is controlled by growth conditions.

Two important phenomena in the regulation of the virulence genes are phase variation and phenotypic modulation.

Phase variation indicates a reversible alteration in the genotype caused by frameshift mutations in which the virulent bacteria simultaneously lose the ability to synthesize toxins and other factors associated with pathogenicity. Erythromycin tolerance has been shown a phase marker caused by extensive alterations in the surface properties between the virulent and the avirulent strains, which confer susceptibility to this antibiotic5. The natural emergence of phase variants in the later stages of infection implies that phase change could be a defense mechanism to escape immune detection, like Salmonella flagellar phase variation where the change of antigenic type helps the bacteria to evade the immune system6.

The other phenomenon termed phenotypic modulation was first observed by Lacey in 19607. It implies repression of the expression of virulence factors except the Tracheal cytotoxin at lower temperature (250C) or in the presence of invitro modulators like SO42, ClO4- and Nicotinic acid8. Using transposonal mutagenesis, a single gene locus responsible for both the phenomena was identified5. This was termed the bvg (Bordetella virulence gene) locus. The bvg genes share homology with a family of prokaryotic regulatory proteins that respond to environmental stimuli.

  • Describe the biologic activities of pertussis toxin

  • Describe the 3 clinical stages of pertussis

  • Describe the clinical manifestations in infants younger than 3 mos of age, in adolescents, and adults

  • Describe features that raise clinical suspicion of pertussis

After 1 to 2 weeks and as the disease progresses, the traditional symptoms of pertussis may appear and include:

  • Paroxysms (fits) of many, rapid coughs followed by a high-pitched “whoop” sound
  • Vomiting (throwing up) during or after coughing fits
  • Exhaustion (very tired) after coughing fits

Both posttussive vomiting  Posttussive means “after cough” and whooping in adults have a low sensitivity and high specificity. The clinical implication is that if an adult patient has posttussive vomiting or whooping, it raises suspicion of pertussis as a differential diagnosis, making both of these good “rule in”
tests.

Posttussive vomiting in children, however, is only moderately sensitive and specific. This factor makes it much less helpful as a clinical diagnostic test than in adults

  • Discuss other infectious causes of a cough that must be differentiated from pertussis

In GENERAL: Viruses and bacteria. The most common cause of a cough is a respiratory tract infection, such as a cold or flu. Respiratory tract infections are usually caused by a virus and may last from a few days to a week. Infections caused by the flu may take a little longer to clear up and may sometimes require antibiotics.

SEE above for prodromal Sx…

  • Discuss laboratory diagnosis of pertussis with PCR testing on nasopharyngeal wash specimens

  • Discuss treatment

Supportive therapy is the mainstay of treatment in patients with active pertussis infection. [23The goals of therapy include limiting the number of paroxysms, observing the severity of cough, providing assistance when necessary, and maximizing nutrition, rest, and recovery. Oxygenation, breathing treatments, and mechanical ventilation should be provided as necessary. Infants should be carefully observed for apnea, cyanosis, or hypoxia.

  • Discuss antimicrobial treatment with azithromycin

SAME AS ABOVE – if given early…

  • Discuss adjunct therapies, isolation, and care of close contacts

Previous studies have shown that antibiotics fail to improve the course of disease unless diagnosed early. Early diagnosis is complicated by the non-diagnostic presentation of disease early in infection.

Two novel approaches – Manipulation of the signaling pathway of sphingosine-1-phosphate, a lipid involved in many immune processes, has shown great promise, but is in its infancy.

Pendrin, a host epithelial anion exchanger upregulated in the airways with B. pertussis infection, appears to drive mucus production and dysregulation of airway surface liquid pH and salinity. In addition to detailing these potential new therapeutic targets, the need for greater focus on the neonatal model of disease is highlighted.

  • Discuss complications

  • Describe the DTaP and Tdap vaccines

Children’s VaccinesDTaP is a vaccine that helps children younger than age 7 develop immunity to three deadly diseases caused by bacteria: diphtheria, tetanus, and whooping cough (pertussis). Tdap is a booster immunization given at age 11 that offers continued protection from those diseases for adolescents and adults.

 

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