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Zalcitabine: It is less toxic and is combined with AZT for advanced HIV
infection.
Stavudine: It is similar to AZT and the major toxicity is dose-related to peripheral
neuropathy.
Lamivudine (Epivir): It is perhaps the best tolerated NRTIs. It is given in the dose of
150 mg two times a day. It is also indicated for the treatment of hepatitis B infection.
It may cause malaise, fatigue, and GI disturbances.
Abacavir (Ziagen): It is a well-tolerated NRTI and has high therapeutic efficacy.
Adverse drug reactions include hypersensitivity reactions in addition to malaise,
headache, and GI disturbances.
2. Non-nucleotide reverse transcriptase inhibitors (NNRTIs): These drugs inhibit
the reverse transcriptase enzyme by binding to its active site. They do require
activation by cellular phosphorylation for their antiretroviral activity. They are
effective only against HIV-1.
Nevirapine (Viramune): It was the first NNRTI approved by the FDA and is the
drug of choice for women during childbearing age and pregnancy. It is well
absorbed and is not affected by food.
Delavirdine (Rescriptor): Its tolerability profile is similar to Nevirapine and it is
used in the treatment of HIV-1 infection in adults. It has high bioavailability and
plasma protein binding capacity. It should be avoided in pregnancy.
Efavirenz (Sustiva): This drug is used in the treatment of HIV-1 infection in adults
and children. It is used in combination with other antiretroviral agents to prevent
the development of resistance.
3. Protease inhibitors (PIs): These drugs act by inhibiting aspartyl protease,
which cleave viral proteins and effectively stop replication. They thus prevent
the maturation of the newly produced virions so that they remain noninfected.
Saquinavir (Invirase): It is the first drug approved under this class of PI, is the least
potent, and is not used alone. It is well tolerated and GI effects like nausea,
diarrhoea, and abdominal pain are very common.
Ritonavir (Norvir): It was approved for the treatment of children with HIV infection
or AIDS.
Indinavir (Crixivan): It is rapidly absorbed, but its bioavailability is reduced with
meals, so it should be taken on an empty stomach. The principal complication of
indinavir is nephrolithiasis.
Nelfinavir (Viracept): It is the best tolerated of the available PIs. The major side
effect is mild to moderate diarrhoea.
4. Entry inhibitors: These are of two types: Fusion inhibitors and CCR5 inhibitors.
Enfuvirtide is a fusion inhibitor that is administered subcutaneously.
Maraviroc is a CCR5 inhibitor that is indicated in patients with only CCR5-tropic
virus. It is used in patients with resistance to one or more other antiretroviral
classes.
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5. Integrase inhibitors: The drugs bind to the integrase enzyme thus blocking the
integration of viral DNA into host DNA. Raltegravir (Isentress) is the approved
drug in this class.
KEY POINTS
• HIV infection is a sexually transmitted disease which damages the immune system.
• One can get infected with HIV through infected blood, semen, or vaginal secretions. It can spread
from an infected mother to child during pregnancy, childbirth, or breastfeeding.
• The most severe stage of HIV (stage 3) is AIDS (acquired immunodeficiency syndrome) and is a
life-threatening condition.
• No vaccine is available to prevent HIV infection.
• Azidothymidine, didanosine, efavirenz, and saquinavir are some of the drugs used for the
treatment of HIV infection.
HIV Infection-associated Opportunistic Infections
Opportunistic infections (OIs) are infections that occur more frequently and with more
severity in HIV patients, and this is due to their weakened immune systems. Due to
effective HIV treatment, OIs are less common in people with HIV now.
Candidiasis: Candidiasis is a frequent manifestation of HIV infection and may
occur early in the disease. Clinically, it is usually characterised by white plaques on
the oral mucosa. If swallowing is difficult or painful, oesophageal involvement may
be suspected. First-line therapy for oral candidiasis is a systemic agent like fluconazole
(50 mg daily for 7 days). An alternative is itraconazole (200 mg once daily).
Cryptococcosis: This illness is caused by infection with the fungus Cryptococcus
neoformans, usually with meningeal involvement in individuals with HIV infection.
For patients who are moderately or severely unwell, amphotericin IV is the first line
therapy.
Toxoplasmosis: The parasite Toxoplasma gondii is a frequent cause of central
nervous system disease in patients with AIDS. The patients may present with
headaches, fever, confusion, seizures, or focal neurological signs and symptoms. Firstline treatment is sulphadiazine and pyrimethamine with folinic acid to prevent
myelosuppression for 6 weeks, followed by maintenance therapy.
Cryptosporidiosis: This is a disease caused by a tiny parasite called Cryptosporidium
parvum and is seen in immunocompromised individuals. Symptoms include
abdominal cramps and severe, chronic, watery diarrhoea.
Tuberculosis (TB): In HIV-positive individuals, Mycobacterium tuberculosis is
characterised by an increased likelihood of reactivation of latent disease, rapid
progression to clinical disease, and more frequent extrapulmonary manifestations of
TB. Treatment should consist of four drugs: Isoniazid, rifampicin, pyrazinamide, and
ethambutol for two months, followed by two drugs: Isoniazid and rifampicin for at
least two months.
Mycobacterium avium complex (MAC): MAC is caused by infection with
different types of Mycobacterium: Mycobacterium avium, Mycobacterium intracellulare, or
Mycobacterium kansasii, and was historically a frequent manifestation of late-stage HIV
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disease. Generally, a combination of clarithromycin and ethambutol is used for
treatment.
Cytomegalovirus (CMV): It is a herpes virus which normally remains dormant, but
in individuals with advanced immunosuppression, reactivation may occur and cause
disease. In the context of HIV infection, the most common sites are retina and GIT.
Pneumocystis jirovecii pneumonia: This fungal infection remains one of the most
common causes of morbidity and mortality in HIV positive individuals. First-line
therapy is high-dose co-trimoxazole for 21 days.
Pneumocystis carinii pneumonia: This infection causes pneumonia in immuno-
compromised individuals. Trimethoprim-sulfamethoxazole is the widely considered
drug of choice.
Kaposi’s sarcoma (KS): This is the most common malignancy in people with HIV
infection.
KS appears as firm pink or purple spots on the skin that can be raised or flat. KS can
be life-threatening when it affects organs inside the body, such as the lungs, lymph
nodes, or intestines. The liposomal anthracyclines and taxanes are now the mainstays
of systemic chemotherapy for Kaposi’s sarcoma.
Lymphomas: The most common lymphomas in patients with HIV infection are
high-grade B-cell (non-Hodgkin’s) types. The risk of developing primary CNS
lymphomas is very high in HIV patients as compared to the general population.
However, with the advent of highly active antiretroviral therapy (HAART), this risk
has been considerably reduced.
KEY POINTS
• Opportunistic infections (OIs) are infections that occur more frequently in HIV patients due to their
weakened immune systems.
• Some of OIs are candidiasis, cryptococcosis, tuberculosis, toxoplasmosis, pneumonia, Kaposi’s
sarcoma and lymphomas.
8.8 VIRAL INFECTIONS (SARS-CoV-2)
Severe Acute Respiratory Syndrome (SARS)
Severe acute respiratory syndrome (SARS) is a viral respiratory disease caused by a
SARS-associated coronavirus. It first appeared in November 2002 in Southern China
and has since spread to over 24 countries in Asia, Europe, North America, and South
America. Since 2004, there have been no new cases of SARS, and the risk is relatively
low.
Aetiology
SARS is caused by a strain of coronavirus, the same family of viruses that cause the
common cold.
Pathophysiology
SARS is an airborne virus that, like the common cold and influenza, can be spread
through small droplets of saliva. When a person with SARS coughs or sneezes without
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covering his or her mouth, respiratory droplets containing living viruses can spray up
to 3 feet and infect another person’s mucous membranes. SARS can also be spread
indirectly through surfaces (doorknobs, telephones, etc.) touched by someone who is
infected with the virus.
Clinical Manifestations
SARS usually begins with flu-like signs and symptoms such as fever, chills, muscle
aches, and headaches. It then progresses to include one or more of the following
symptoms:
• Fever of 100.5°F (38°C) or higher
• Dry cough
• Sore throat
• Difficulty in breathing
• Shortness of breath
• Pneumonia
• Diarrhoea (for 10 to 20 percent of patients)
Non-pharmacological Management
Currently, no vaccine is available to prevent SARS. Hence, the following guidelines
are recommended to prevent the infection:
• Wash your hands often with soap and water, or use an alcohol-based hand sanitizer.
• Do not touch your eyes, nose, or mouth with dirty hands.
• Wear disposable gloves if you come into contact with a person’s body fluids or
faeces.
• Wipe surfaces like countertops with disinfectants, and wash personal items like
towels, clothes, or utensils with soap and hot water.
• If you are around someone with SARS, wear a surgical mask to cover your nose
and mouth.
Follow all precautions for at least 10 days after the person’s signs and symptoms
have disappeared. Keep children home from school if they develop a fever or
respiratory symptoms within 10 days of being exposed to someone with SARS.
Pharmacological Management
People with SARS only receive supportive care, such as oxygen and fluids to alleviate
symptoms and antibiotics to prevent or treat secondary infections. There are no drugs
that work against the virus that causes SARS.
KEY POINTS
• Severe acute respiratory syndrome (SARS) is a viral respiratory disease caused by a SARSassociated coronavirus.
• SARS usually begins with flu-like signs and symptoms such as fever, chills, muscle aches, and
headaches.
• No vaccine is available to prevent SARS.
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SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible
and pathogenic coronavirus that emerged in late 2019 and has caused a pandemic of
acute respiratory diseases known as “coronavirus disease 2019” (COVID-19),
endangering human health and public safety.
At the end of 2019, a new coronavirus known as SARS-CoV-2 emerged in the
city of Wuhan, China, causing an outbreak of unusual viral pneumonia. This novel
coronavirus disease, also known as COVID-19, has spread rapidly throughout the
world due to its high transmissibility. It has far surpassed SARS (severe acute
respiratory syndrome) and MERS (Middle East respiratory syndrome) in terms of
both the number of infected people and the geographic range of epidemic areas.
The ongoing outbreak of COVID-19 has posed a great threat to global public
health.
Aetiology
COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). Coronaviruses are a group of viruses that infect a wide range of animals and
can cause mild to severe respiratory infections in humans.
Pathophysiology
SARS-CoV-2 is an enveloped coronavirus with spike (S) glycoprotein, envelope (E),
and membrane (M) proteins coating the viral envelope. The S protein is responsible
for host cell binding and entry. SARS-CoV-2 could spread through coughing and
sneezing. The virus enters the respiratory tract and attacks alveolar epithelial type 2
(AT2) cells in the lungs. The first step in infection is for the virus to bind to host cells
(AT2 cells) via its target receptor ACE 2. The receptor binding domain of the S protein
is found in the S1 subunit, which binds to the peptidase domain of angiotensinconverting enzyme 2 (ACE 2). The S2 subunit of SARS-CoV-2 is highly conserved and
is thought to be a potential antiviral target. The structure of the virus and its
replication cycle are described in Fig 8.3.
The virus’s active replication and release in lung cells causes non-specific symptoms
such as fever, myalgia, headache, and respiratory symptoms. The distribution of
ACE 2 receptors in different tissues may explain the different sites of infection and
patient symptoms. The ACE 2 receptor, for example, is found on the epithelium of
other organs, such as the intestine, as well as endothelial cells in the kidney and blood
vessels, which may explain gastrointestinal symptoms and cardiovascular complications.
Following viral entry, the initial inflammatory response attracts virus-specific T cells
to the site of infection, where infected cells are eliminated before the virus spreads,
resulting in recovery in the vast majority of people. SARS-CoV-2 causes an abnormal
host immune response in patients who develop severe disease.
To stimulate macrophages, the virus also releases specific inflammatory mediators.
When macrophages become activated, they release cytokines (IL-1, IL-6, and TNF) and
chemokines (CXCL10 and CCL2) into the bloodstream. Vasodilation and increased
capillary permeability are caused by the release of these molecules. Plasma leakage into
the interstitial spaces of the alveolar cells causes it to accumulate and compress around
the alveoli. These events eventually result in alveolar collapse and impaired gas
exchange.
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Fig. 8.3: (1) The virus binds to ACE 2 as the host target cell receptor in synergy with the host’s
transmembrane serine protease 2 (cell surface protein), which is principally expressed in the airway
epithelial cells and vascular endothelial cells. This leads to membrane fusion and releases the viral
genome into the host cytoplasm (2). Stages (3–7) show the remaining steps of viral replication,
leading to viral assembly, maturation, and virus release.
The presence of mucus plugs with fibrinous exudate in the respiratory tract is a
distinguishing feature of COVID-19, which may explain the severity of COVID-19
even in young adults. This could be due to an increase in the production of proinflammatory cytokines, which build up in the lungs and eventually damage the lung
parenchyma.
Septic shock and multi-organ dysfunction are also observed in some patients.
The cardiovascular system, for example, is frequently involved early in COVID-19
disease, as evidenced by the release of highly sensitive troponin and natriuretic
peptides.
Clinical Manifestations
Fever, dry cough, fatigue, and, in severe cases, dyspnoea are typical symptoms of
coronavirus disease 2019 (COVID-19). Many infections are asymptomatic, especially
in children and young adults, whereas older people and/or people with comorbidities are at a higher risk of severe disease, respiratory failure, and death. The
incubation period is 5 days; severe disease usually appears 8 days after the onset of
symptoms, and critical disease and death occur after around 16 days.
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Diagnosis
1. A fluid swab test is performed on a patient with COVID-19 symptoms to rule out
influenza.
2. Quantitative real-time PCR: Although the sensitivity ranges from 40 to 85 percent,
it is the gold standard diagnostic method for detecting COVID-19.
3. Complete blood picture report: Estimate your RBC, WBC, and platelet counts.
Lymphopenia has been observed in 80% of the patients.
4. Liver function tests: Calculate AST, ALT, and acute-phase proteins to determine
the prognosis of multi-organ failure.
5. Renal function tests: Estimate creatinine and BUN levels to assess kidney perfusion.
6. Procalcitonin levels: A viral infection may result in a bacterial superinfection.
Elevated procalcitonin levels may indicate COVID-19 superinfection.
7. CRP/D-Dimer/Other marker levels: Elevated levels of supporting markers such as
CRP, IL-6, LDH, ferritin, D-dimer, and ESR may indicate an advanced stage of
SARS-CoV-2 infection.
8. Troponin and CK-MB levels: Elevated troponins and CK-MB reveal a lack of proper
perfusion to the heart that can increase mortality.
9. Imaging studies:
a. Chest X-ray (CXR): COVID-19 appears to be ground-glass.
b. CT scan: COVID-19 shows ground-glass opacities, protein consolidation, and
crazy paving pattern (CPP) in the lungs.
c. Ultrasound (US): COVID-19 has pleural line thickenings, increased B-lines,
and consolidation with air bronchogram.
Pharmacological Management
Potential antivirals target the various steps of severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) replication, ranging from receptor binding, entry, and
fusion to replication. Furthermore, immunoglobulin-based and immunomodulatory
drugs are also potential therapeutics. The treatment consists of:
Fluid treatment: Providing IV fluids such as normal saline, lactate ringer’s solution,
and oral fluids can help control the perfusion rate by preventing the lungs from being
overloaded.
Fever control: It can be achieved by administering paracetamol.
Hydroxychloroquine (HCQ): HCQ is an anti-antimalarial drug that may inhibit the
synthesis of new SARS-CoV-2.
Replication indicators: These include remdesivir (GS-5734), favilavir (T-705),
ribavirin, lopinavir, and ritonavir. Remdesivir was a drug used for Ebola virus
treatment as it inhibited RNA dependent RNA polymerase. It has previously been
shown to inhibit the replication of SARS-CoV and MERS-CoV. It may also have
therapeutic benefit on SARS-CoV-2 replication.
Protease inhibitors (ritonavir and lopinavir): These drugs may inhibit the
conversion of various polyproteins into the different components (S, M, E, HE, and
enzymes) of SARS-CoV-2.
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Immunomodulatory agents: SARS-CoV-2 causes a strong immune response that
can lead to cytokine storm syndrome. As a result, immunomodulatory agents that
inhibit the excessive inflammatory response could be a potential COVID-19 adjunctive
therapy. Corticosteroids can be used to reduce inflammation by inhibiting the
formation of leukotrienes and prostaglandins via phospholipase 2 (PGE2). Dexamethasone
is a corticosteroid that is commonly used to treat inflammation due to its antiinflammatory and immunosuppressive properties.
Tocilizumab and sarilumab, two types of interleukin-6 (IL-6) receptor-specific
antibodies previously used to treat rheumatoid arthritis and cytokine release
syndrome, demonstrated efficacy in the treatment of severe COVID-19 by attenuating
the cytokine storm. Tocilizumab inhibits IL-6’s inflammatory role on alveolar
capillaries as well as the accumulation of interstitial fluids.
Immunoglobulin therapy: Convalescent plasma treatment is another potential
COVID-19 adjunctive therapy.
Tetracyclines: Tetracyclines are antibiotics that bind to the matrix metalloproteinases
(MMPs) and may reduce SARS-CoV-2 infiltration. The coronaviruses utilise MMPs for
their replication, infiltration, and cell-cell adhesion.
Molnupiravir: It is the first oral, direct-acting antiviral that has been shown to be
highly effective in reducing nasopharyngeal SARS-CoV-2 infectious virus and viral RNA.
Vitamin D: Vitamin D supplementation may reduce pro-inflammatory
cytokines.
Vaccines: Vaccination is the most effective method for a long-term strategy for
prevention and control of COVID-19 in the future.
Prevention of COVID-19
The following are the simple steps one can take to help prevent the spread of COVID19 and protect oneself and others:
• Getting vaccinated is the most effective way to prevent the spread of SARS-CoV-2,
the virus that causes COVID-19.
• Everyone aged 2 years and older should properly wear a face mask in public
settings.
• Because close person-to-person contact appears to be the primary mode of
transmission, social distancing remains an important method of mitigating spread.
This social distancing should be done by keeping a distance of about 6 feet from
others in public places. This distance will keep you from coming into direct contact
with respiratory droplets caused by coughing or sneezing.
• Good hygiene is an important habit that aids in the prevention of the spread of
COVID-19. For this, washing hands frequently with soap and water for at least
20 seconds or using hand sanitizer, especially after being in a public place or after
blowing one’s nose, coughing, or sneezing.
• Surfaces such as tables, doorknobs, light switches, countertops, handles, desks,
phones, keyboards, toilets, faucets, and sinks should be disinfected frequently.
• Travel can increase the spread of COVID-19 and it is better to avoid non-essential
travel during the pandemic.
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• If you think you may have been exposed to a person with COVID-19 and have
symptoms such as fever or chills, cough, shortness of breath or difficulty breathing,
fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat,
congestion or runny nose, nausea or vomiting, or diarrhoea, you should visit a
doctor and get tested.
KEY POINTS
• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and
pathogenic coronavirus that emerged in late 2019 and has caused a pandemic COVID-19.
• The typical symptoms of COVID-19 are fever, dry cough, fatigue, and, in severe cases, dyspnoea.
• Getting vaccinated is the most effective way to prevent the spread of SARS-CoV-2, the virus that
causes COVID-19.
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9
Musculoskeletal Disorders
9.1 RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) is a very common systemic inflammatory disease which
affects joints and extra-articular organs. If it is not treated early, it may lead to joint
destruction, disability, and premature death.
Aetiopathogenesis
Underlying causative factors are not clear for rheumatoid arthritis but following risk
factors are associated with it.
• Hormones: It has been observed that females are more likely to develop rheumatoid
arthritis than males (3:1)
• Age: RA develops with increasing age, at the peak of 35–50 years of age
• Genetic factors: Genetic factors contribute to 53–65% of developing risk factors for
RA. The HLA (human leukocyte antigen)—DR4 allele is associated with both
development and severity of RA.
• Cigarette smoking: Smokers are more likely to have extra-articular manifestations
and to experience treatment unresponsiveness.
• Stress: Stress also affects RA onset and its progression. Chronic presence of minor
stressors like daily hassle, work and relationship stress, financial pressure; rather
than more stressful events may affect immune response and RA activity.
Pathological changes in development of RA include infiltration of a variety of
inflammatory cells into the joint. The acellular synovial membrane becomes highly
vascularised and hypertrophied which creates thickened, inflamed membrane
lining called pannus. Synovial fibroblast becomes proliferated with an influx of
inflammatory cells like T cells, B cells, macrophages, and plasma cells. Cytokines like
TNF-, interleukin-1, interleukin-6 and GM-CSF are released by these cells that release
proteolytic enzymes and ultimately destruction of bone and cartilage. Inflammatory
cells like T cells, B cells, macrophages, and plasma cells. These cells release cytokines
like tumour necrosis factor (TNF-), interleukin-1, interleukin-6, and granulocyte
macrophage colony stimulating factor (GM-CSF) that secrete proteolytic enzymes
which ultimately causes destruction of bones and cartilages.
Clinical Manifestations
Rheumatoid arthritis may be presented in different patterns—polyarticular arthritis
(arthritis in which many joints are involved) or monoarticular arthritis. Extra-articular
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