Dengue Fever

Introduction:

Dengue is a febrile illness caused by infection with one of four dengue viruses (DENV) transmitted by Aedes aegypti or Aedes albopictus mosquitoes during the taking of a blood meal. Infection may be asymptomatic or present with a broad range of clinical manifestations including a mild febrile illness to a life-threatening shock syndrome. Numerous viral, host, and vector factors are thought to impact risk of infection, disease, and disease severity.

There are four closely related but serologically distinct DENV types of the genus Flavivirus, called DENV-1, DENV-2, DENV-3, and DENV-4. There is transient cross-protection among the four DENVs, which weakens and disappears over the months following infection; therefore, individuals living in a dengue-endemic area with all types co-circulating are at risk for infection with any and all DENV types.

The Aedes mosquito:

Dengue viruses are transmitted by the bite of an infected female Aedes (subgenus Stegomyia) mosquito. Both males and females require nectar for energy. Females require a blood meal as a source of appropriate protein for egg development. Globally, Aedes aegypti is the predominant highly efficient mosquito vector for dengue infection, but the Asian tiger mosquito, Aedes albopictus, and other Aedes species can also transmit dengue with varying degrees of efficiency.

 Dengue fever :

DF (also known as "break-bone fever") is an acute febrile illness defined by the presence of fever and two or more of the following but not meeting the case definition of DHF. (see 'Dengue hemorrhagic fever' below):

●Headache

●Retro-orbital or ocular pain

●Myalgia and/or bone pain

●Arthralgia

●Rash

●Hemorrhagic manifestations (eg, positive tourniquet test, petechiae, purpura/ecchymosis, epistaxis, gum bleeding, blood in emesis, urine, or stool, or vaginal bleeding)

●Leukopenia   

Dengue hemorrhagic fever :

The cardinal feature of DHF is plasma leakage due to increased vascular permeability as evidenced by hemoconcentration (≥20 percent rise in hematocrit above baseline), pleural effusion, or ascites. DHF is also characterized by fever, thrombocytopenia, and hemorrhagic manifestations (all of which may also occur in the setting of DF). (See 'Dengue fever' above.)

In the setting of DHF, the presence of intense abdominal pain, persistent vomiting, and marked restlessness or lethargy, especially coinciding with defervescence, should alert the clinician to possible impending DSS. (See 'Dengue shock syndrome' below.)

The criteria for DHF comprise a narrow definition that does not encompass all patients with clinically severe or complicated DENV infections.

According to the guidelines, a DHF diagnosis requires all of the following be present:

●Fever or history of acute fever lasting 2 to 7 days, occasionally biphasic

●Hemorrhagic tendencies evidenced by at least one of the following:

•A positive tourniquet test – The tourniquet test is performed by inflating a blood pressure cuff on the upper arm to a point midway between the systolic and diastolic pressures for 5 minutes. A test is considered positive when 10 or more petechiae per 2.5 cm (1 inch) square are observed. The test may be negative or mildly positive during the phase of profound shock. It usually becomes positive, sometimes strongly positive, if the test is conducted after recovery from shock. It is estimated that the tourniquet test is positive in 80 percent of patients with dengue.

•Petechiae, ecchymoses, or purpura.

•Bleeding from the mucosa, gastrointestinal tract, injection sites, or other locations.

•Hematemesis or melena.

●Thrombocytopenia (100,000 cells per mm3 or less) – This number represents a direct count using a phase-contrast microscope (normal is 200,000 to 500,000 per mm3). In practice, for outpatients, an approximate count from a peripheral blood smear is acceptable. In healthy individuals, 4 to 10 platelets per oil-immersion field (100x; the average of the readings from 10 oil-immersion fields is recommended) indicates an adequate platelet count. An average of 3 platelets per oil-immersion field is considered low (ie, 100,000 per mm3).

●Evidence of plasma leakage due to increased vascular permeability manifested by at least one of the following:

•A rise in the hematocrit equal to or greater than 20 percent above average for age, sex, and population.

•A drop in the hematocrit following volume-replacement treatment equal to or greater than 20 percent of baseline.

•Signs of plasma leakage such as pleural effusion, ascites, and hypoproteinemia.

Dengue shock syndrome :

DSS is DHF with marked plasma leakage that leads to circulatory collapse (shock) as evidenced by narrowing pulse pressure or hypotension.

For a diagnosis of DSS, all of the above four criteria for DHF must be present plus evidence of circulatory failure manifested by:

●Rapid and weak pulse.

●Narrow pulse pressure (20 mmHg [2.7 kPa]) or manifested by:

•Hypotension for age – Hypotension is defined to be a systolic pressure 80 mmHg (10.7 kPa) for those less than 5 years of age or 90 mmHg (12.0 kPa) for those greater than or equal to 5 years of age. Note that narrow pulse pressure is observed early in the course of shock, whereas hypotension is observed later or in patients who experience severe bleeding.

•Cold, clammy skin and restlessness.

Dengue without warning signs:

A presumptive diagnosis of dengue infection may be made in the setting of residence in or travel to an endemic area plus fever and two of the following [9]:

●Nausea/vomiting

●Rash

●Headache, eye pain, muscle ache, or joint pain

●Leukopenia

●Positive tourniquet test

Dengue with warning signs :

Dengue with warning signs of severe infection includes dengue infection as defined above in addition to any of the following [9]:

●Abdominal pain or tenderness

●Persistent vomiting

●Clinical fluid accumulation (ascites, pleural effusion)

●Mucosal bleeding

●Lethargy or restlessness

●Hepatomegaly >2 cm

●Increase in hematocrit concurrent with rapid decrease in platelet count

Severe dengue :

Severe DENV infection includes infection with at least one of the following:

●Severe plasma leakage leading to:

•Shock

•Fluid accumulation with respiratory distress

●Severe bleeding (as evaluated by clinician)

●Severe organ involvement:

•Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥1000 units/L

•Impaired consciousness

•Organ failure

Signs and symptoms :

On average, dengue becomes symptomatic after a 4- to 10-day incubation period (range, 3-14 days). Dengue symptoms usually last 2-7 days.

Many individuals with dengue may be asymptomatic. Many patients with dengue experience a prodrome of chills; rash, including erythematous mottling of the skin; and facial flushing, which may last 2-3 days. Children younger than 15 years who have dengue usually have a nonspecific febrile syndrome, which may be accompanied by a maculopapular rash. Dengue should be suspected in individuals who present with high fever (104°F/40°C), retro-orbital headache, muscle and joint pain, nausea, lymphadenopathy, vomiting, and rash and who have traveled within 2 weeks of symptom onset to an area where appropriate vectors are present and dengue transmission may be occurring.

Accompanying symptoms in patients with dengue may include any of the following:

Fever

Headache

Retro-orbital pain

Severe myalgias: Especially of the lower back, arms, and legs

Arthralgias: Usually of the knees and shoulders

Nausea and vomiting (diarrhea is rare)

Rash: A maculopapular or macular confluent rash over the face, thorax, and flexor surfaces, with islands of skin sparing

Weakness, malaise, and lethargy

Altered taste sensation

Anorexia

Sore throat

Mild hemorrhagic manifestations (eg, petechiae, bleeding gums, epistaxis, menorrhagia, hematuria)

Lymphadenopathy

Diagnosis :

Demonstration of a fourfold or greater change in reciprocal immunoglobulin G (IgG) or IgM antibody titers to 1 or more dengue virus antigens in paired serum samples

Demonstration of dengue virus antigen in autopsy tissue via immunohistochemistry or immunofluorescence or in serum samples via enzyme immunoassay (MAC-ELISA, IgG ELISA, nonstructural protein 1 [NS1] ELISA, EIA)

Detection of viral genomic sequences in autopsy tissue, serum, or cerebral spinal fluid (CSF) samples via reverse-transcriptase polymerase chain reaction (RT-PCR) assay: RT-PCR provides earlier and more specific diagnosis.

Less frequently, isolation of the dengue virus from serum, plasma, leukocytes, or autopsy samples

PREVENTION :

Personal protection from infection

Mosquito repellants — Issues related to personal protection for prevention of mosquito bites are discussed separately. (See "Prevention of arthropod and insect bites: Repellents and other measures".)

Insecticide spraying — Distribution of insecticide-treated curtains was successful in reducing populations of A. aegypti mosquitoes for up to 18 months in several studies and was associated with reduced human and mosquito infections with DENV in one region, although use of the curtains declined with time. Insecticide spraying in response to dengue outbreaks is not highly effective, since A. aegypti mosquitoes frequently breed inside houses.

Vaccine development — Infection with one DENV type provides long-term protection against reinfection with that same type, supporting the feasibility of an effective dengue vaccine. 

Treatment :

No specific treatment for dengue fever exists.

While recovering from dengue fever, drink plenty of fluids. Call your doctor right away if you have any of the following signs and symptoms of dehydration:

Decreased urination

Few or no tears

Dry mouth or lips

Lethargy or confusion

Cold or clammy extremities

The over-the-counter (OTC) drug acetaminophen (Tylenol, others) can help reduce muscle pain and fever. But if you have dengue fever, you should avoid other OTC pain relievers, including aspirin, ibuprofen (Advil, Motrin IB, others) and naproxen sodium (Aleve). These pain relievers can increase the risk of dengue fever bleeding complications.

If you have severe dengue fever, you may need:

Supportive care in a hospital

Intravenous (IV) fluid and electrolyte replacement

Blood pressure monitoring

Transfusion to replace blood loss

 Breast Cancer

Breast cancer is the common term for a set of breast tumor subtypes with distinct molecular and cellular origins and clinical behavior. Most of these are epithelial tumors of ductal or lobular origin (see the image below). Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women and the leading cause of cancer death among women.

 Risk Factors for Breast Cancer

Factors that may affect breast cancer risk include the following:

• Age: The strongest risk factor for breast cancer is age. Median age at diagnosis is about 60 years.

• Family history: Having a 1st-degree relative (mother, sister, daughter) with breast cancer doubles or triples risk of developing the cancer, but breast cancer in more distant relatives increases risk only slightly. When ≥ 2 1st-degree relatives have breast cancer, risk may be 5 to 6 times higher.

• Breast cancer gene mutation: About 5 to 10% of women with breast cancer carry a mutation in one of the two known breast cancer genes, BRCA1 or BRCA2. The risk of developing breast cancer by age 80 is about 72% with a BRCA1 mutation and about 69% with a BRCA2 mutation. Women with BRCA1 mutations also have an approximate 44% lifetime risk of developing ovarian cancer; risk among women with BRCA2 mutations is about 17% (3, 4). Women without a family history of breast cancer in at least two 1st-degree relatives are unlikely to carry this mutation and thus do not require screening for BRCA1 and BRCA2 mutations. Men who carry a BRCA mutation have a 1 to 2% lifetime risk of developing breast cancer. The mutations are more common among Ashkenazi Jews. Women with BRCA1 or BRCA2 mutations require closer surveillance or preventive measures, such as screening with both mammography and MRI, taking tamoxifen or raloxifene, or undergoing risk-reducing mastectomy.

• Personal history: Having had in situ or invasive breast cancer increases risk. Risk of developing cancer in the contralateral breast after mastectomy is about 0.5 to 1%/year of follow-up.

• Gynecologic history: Early menarche, late menopause, or late first pregnancy increases risk. Women who have a first pregnancy after age 30 are at higher risk than those who are nulliparous.

• Breast changes: History of a lesion that required a biopsy is associated with a slightly increased risk. Women with multiple breast masses but no histologic confirmation of a high-risk histology should not be considered at high risk. Benign lesions associated with a slightly increased risk of developing invasive breast cancer include complex fibroadenoma, moderate or florid hyperplasia (without atypia), sclerosing adenosis, and papilloma. Risk is about 4 or 5 times higher than average in patients with atypical ductal or lobular hyperplasia and about 10 times higher if they have a family history of invasive breast cancer in a 1st-degree relative. Increased breast density seen on screening mammography is associated with a 1.2- to 2.1-fold increased risk of breast cancer.

• Lobular carcinoma in situ (LCIS): Having LCIS increases the risk of developing invasive carcinoma in either breast by about 7 to 12 times ; invasive carcinoma develops in about 1 to 2% of patients with LCIS annually.

• Use of oral contraceptives: Study results vary regarding the use of oral contraceptives and risk of breast cancer. Some studies have found a small increased risk in current or recent users.

• Hormone therapy: Menopausal hormone (estrogen plus a progestin) therapy appears to increase risk modestly after only 3 years of use. After 5 years of use, the increased risk is about 7 or 8 more cases per 10,000 women for each year of use (about a 24% increase in relative risk). Use of estrogen alone does not appear to increase risk of breast cancer (as reported in the Women's Health Initiative). Selective estrogen-receptor modulators (eg, raloxifene) reduce the risk of developing breast cancer.

• Radiation therapy: Exposure to radiation therapy before age 30 increases risk. Mantle-field radiation therapy for Hodgkin lymphoma about quadruples risk of breast cancer over the next 20 to 30 years.

• Diet: Diet may contribute to development or growth of breast cancers, but conclusive evidence about the effect of a particular diet (eg, one high in fats) is lacking. Obese postmenopausal women are at increased risk, but there is no evidence that dietary modification reduces risk. For obese women who are menstruating later than normal, risk may be decreased.

• Lifestyle factors: Smoking and alcohol may contribute to a higher risk of breast cancer. Women are counseled to stop smoking and to reduce alcohol consumption. In epidemiologic studies, alcohol intake is associated with a higher risk of breast cancer; however, causality is difficult to establish. The American Cancer Society recommends no more than one alcoholic drink a day for women. 

• Pathology of Breast Cancer : 

• Most breast cancers are epithelial tumors that develop from cells lining ducts or lobules; less common are nonepithelial cancers of the supporting stroma (eg, angiosarcoma, primary stromal sarcomas, phyllodes tumor).
• Cancers are divided into carcinoma in situ and invasive cancer.

Carcinoma in situ is proliferation of cancer cells within ducts or lobules and without invasion of stromal tissue. There are 2 types:

Ductal carcinoma in situ (DCIS): About 85% of carcinoma in situ are this type. DCIS is usually detected only by mammography. It may involve a small or wide area of the breast; if a wide area is involved, microscopic invasive foci may develop over time.

Lobular carcinoma in situ (LCIS): LCIS is often multifocal and bilateral. There are 2 types: classic and pleomorphic. Classic LCIS is not malignant but increases risk of developing invasive carcinoma in either breast. This nonpalpable lesion is usually detected via biopsy; it is rarely visualized with mammography. Pleomorphic LCIS behaves more like DCIS; it should be excised to negative margins.

Invasive carcinoma is primarily adenocarcinoma. About 80% is the infiltrating ductal type; most of the remaining cases are infiltrating lobular.

Rare types include medullary, mucinous, metaplastic, and tubular carcinomas. Mucinous carcinoma tends to develop in older women and be slow growing. Women with most of these rare types of breast cancer have a much better prognosis than women with other types of invasive breast cancer. However, the prognosis for women with metaplastic breast cancer is significantly worse than other types of ductal breast cancer.

Inflammatory breast cancer is a fast-growing, particularly aggressive, and often fatal cancer. Cancer cells block the lymphatic vessels in breast skin; as a result, the breast appears inflamed, and the skin appears thickened, resembling orange peel (peau d’orange). Usually, inflammatory breast cancer spreads to the lymph nodes in the armpit. The lymph nodes feel like hard lumps. However, often no mass is felt in the breast itself because this cancer is dispersed throughout the breast.

Pathophysiology of Breast Cancer:

Breast cancer invades locally and spreads through the regional lymph nodes, bloodstream, or both. Metastatic breast cancer may affect almost any organ in the body—most commonly, lungs, liver, bone, brain, and skin. Most skin metastases occur near the site of breast surgery; scalp metastases are uncommon.

Hormone receptors:

Estrogen and progesterone receptors, present in some breast cancers, are nuclear hormone receptors that promote DNA replication and cell division when the appropriate hormones bind to them. Thus, drugs that block these receptors may be useful in treating tumors with the receptors. About two thirds of postmenopausal patients with cancer have an estrogen receptor–positive (ER+) tumor. Incidence of ER+ tumors is lower among premenopausal patients.

Another cellular receptor is human epidermal growth factor receptor 2 (HER2; also called HER2/neu or ErbB2); its presence correlates with a poorer prognosis at any given stage of cancer. In about 20% of patients with breast cancer, HER2 receptors are overexpressed. Drugs that block these receptors are part of standard treatment for these patients.

Breast cancer genes:

BRCA1 and BRCA2 gene mutations increase the risk of developing breast cancer to 70%. Prophylactic bilateral mastectomy reduces the risk of breast cancer by 90% and should be offered to women with a BRCA mutation. Other genetic mutations that increase the risk of developing breast cancer include mutations in CHEK2, PALB2, ATM, RAD51C, RAD51D, BARD1, and TP53, which are usually included in panel genetic testing.

Symptoms and Signs of Breast Cancer

Many breast cancers are discovered as a mass by the patient or during routine physical examination or mammography. Infrequently, the presenting symptom is breast enlargement or a nondescript thickening of the breast. Breast pain may be present but is almost never the sole presenting symptom of breast cancer.

Some types of breast cancer manifest with notable skin changes:

Paget disease of the nipple is associated with an underlying in situ or invasive carcinoma and manifests as skin changes, including erythema, crusting, scaling, and discharge; these changes usually appear so benign that the patient ignores them, delaying diagnosis for a year or more. About 50% of patients with Paget disease of the nipple have a palpable mass at presentation.

Inflammatory breast cancer manifests as erythema and enlargement of the breast, often without a mass, and skin may be discolored or appear thickened, resembling orange peel (peau d’orange). A nipple discharge is common.

A few patients with breast cancer present with signs of metastatic disease (eg, pathologic fracture, abdominal pain, jaundice, dyspnea).

A common finding during physical examination is asymmetry or a dominant mass—a mass distinctly different from the surrounding breast tissue. Diffuse fibrotic changes in a quadrant of the breast, usually the upper outer quadrant, are more characteristic of benign disorders; a slightly firmer thickening in one breast but not the other may be a sign of cancer.

More advanced breast cancers are characterized by one or more of the following:

Fixation of the mass to the chest wall or to overlying skin

Satellite nodules or ulcers in the skin

Matted or fixed axillary lymph nodes suggest tumor spread, as does supraclavicular or infraclavicular lymphadenopathy.

Change in breast size or shape

Skin dimpling or skin changes

Recent nipple inversion or skin change, or nipple abnormalities

Single-duct discharge, particularly if blood-stained

Axillary lump

    

 

Diagnosis of breast cancer

Breast cancer is often first detected as an abnormality on a mammogram before it is felt by the patient or health care provider.

1.Clinical examination

2.Imaging

3.Needle biopsy

4.Physical examination: The following physical findings should raise concern:

Lump or contour change

Skin tethering

Nipple inversion

Dilated veins

Ulceration

Paget disease

Edema or peau d’orange

Screening

Breast self-examination

Mammography

Ultrasonography

Magnetic resonance imaging

Treatment of Breast Cancer

Surgery

Usually radiation therapy

Systemic therapy: Endocrine therapy, chemotherapy, or both

 West Nile Infections Rising in the US

West Nile virus

West Nile virus (WNV) is a single-stranded RNA virus that causes West Nile fever. It is a member of the family Flaviviridae, from the genus Flavivirus, which also contains the Zika virus, dengue virus, and yellow fever virus. The virus is primarily transmitted by mosquitoes, mostly species of Culex. The primary hosts of WNV are birds, so that the virus remains within a "bird–mosquito–bird" transmission cycle.The virus is genetically related to the Japanese encephalitis family of viruses.

Realm: Riboviria

Kingdom: Orthornavirae

Phylum: Kitrinoviricota

Class: Flasuviricetes

Order: Amarillovirales

Family: Flaviviridae

Genus: Flavivirus

Species: West Nile virus

Several signs are pointing to an impending surge in the number of human cases of West Nile virus in several regions of the United States.

West Nile virus is spread by infected mosquitoes and currently there is no cure or virus-specific treatment. In rare cases, it can be deadly. It can infect humans, birds, horses, and other mammals.

West Nile Virus is the leading cause of mosquito-borne disease in the continental US. And as of August 8, 126 human cases had been identified across 22 states, according to the Centers for Disease Control and Prevention (CDC).

Vicki Kramer, PhD, chief of vector-borne diseases in the California Department of Public Health, said, "Particularly here in California, it's peak risk right now."

She said scientists there are seeing higher mosquito and infected mosquito numbers.

"Peak Risk Right Now"

Dead birds are tested for the virus and by August 4, 181 of the 913 birds tested in California have been positive, three times the total testing positive by this time in 2022.

"Last year at this time, we had 60 positive dead birds out of 817 tested," Kramer said.

Severe flooding and high heat can contribute to the rise in mosquito populations and many parts of the country have seen plenty of both.

One of the ways scientists track infected mosquito patterns in California is by using flocks of strategically placed sentinel chickens.

"Chickens are a mosquito magnet," Kramer said.

Chickens don't get sick with the virus, but they do build antibodies to it. Surveillance teams check their blood every other week to track the virus.

Daniel Pastula, MD, MHS, chief of neuroinfectious diseases and global neurology at the University of Colorado School of Medicine and the Colorado School of Public Health, says the state is watching troubling signs as well.

"The concern this year," Pastula said, "particularly along the Front Range in Colorado, is we've found many more mosquitoes [that are] positive for West Nile earlier in the season compared with other years."

"We're bracing for higher-than-baseline human cases," he said.

Asked about this year's first human case reported in Toronto, Canada, a region with a long winter and low incidence of the virus, he said that provides a further example that people need to be prepared even in climates not known to be mosquito-dense.

He added, however, that climate is only one factor in the severity of the season. Others include birds' immunity and migratory patterns.

Pastula said that fluctuations in temperature and rainfall are rising with climate change and are disrupting normal baseline levels of West Nile.

"That shows we need to be prepared for West Nile virus and other mosquito-borne diseases in any place in North America or really the world. We recently saw malaria cases in the southern United States. It just shows you how dangerous mosquitoes can be."

Avoid Mosquito Bites

Pastula and Kramer list the precautions people can take to protect themselves from West Nile virus:

Limit outdoor exposure particularly at dusk and dawn

Wear protective clothing

Use EPA-approved insect repellent

Repair window screens so mosquitoes can't fly through

Dump and drain standing water on your property and maintain swimming pool

Pastula notes that summer is the time human cases start to mount — typically from July and August to the first hard freeze.

"We have been warning people here up and down the Front Range of Colorado to take prevention very seriously," Pastula said.

He pointed out that 80% who are infected with West Nile will have no symptoms.

About 20% will have flu-like illness — high fever, body and joint aches, rash, diarrhea, or headaches. Symptoms may last for weeks. About 1% of the time, he says, people can get neuroinvasive West Nile.

Pastula explains that the virus can infect the covering of the brain and spinal cord causing meningitis with very high fever, severe headaches, stiff neck, and sensitivity to light.

So far this year, there have been 89 neuroinvasive cases reported nationally, according to the CDC.

With West Nile encephalitis, the virus "can infect the brain itself causing altered mental status, movement disorders, or weakness," Pastula said.

Sometimes it can infect the gray matter of the spinal cord causing a West Nile virus poliomyelitis, which brings polio-like symptoms.

"The West Nile encephalitis and poliomyelitis can cause permanent deficits or even death," he said. "It's uncommon but it's not trivial."

Several vaccine candidates are in development, Pastula says, but none has reached clinical trials. Part of the reason for that, he says, is that scientists must be able to predict the timing of an outbreak.

"We're not really great at predicting outbreaks," he said.

Although the risk for neuroinvasive disease is small, it can be higher in certain groups, he says — those who are over age 60 years or are immunocompromised; those who have diabetes, cancer, or kidney disease; or those who have undergone organ transplants.

Those infected should see a healthcare professional and may be able to get relief with the usual medications for flu-like illness.

Some with severe infection may need to go to the hospital, Pastula said.