TORCH(Z) – Congenital Infections

By Jeremy Aguinaldo
May 16, 2017

Figure 1: My nephew Gabriel Andres Doromal

I was fortunate to witness the delivery of a newborn from a young couple in a hospital in Brooklyn, who were excited at the thought of their first child coming into the world. The happiness in the room was palpable. The mother, drenched in sweat and her hair in disarray, was beaming with joy. The father was incessantly taking photos, speaking rapidly to his wife, who cared about nothing on what he had to say. She was preoccupied with the newest member of their family. With the doctor delivering the baby, the nurse providing support and assistance, the anesthesiologist administering drugs, the technician to setup the instruments that may be needed, and the naive medical student trying to be useful; the old saying that “It takes a village to raise a baby,” holds true.

I am at the point in my life where most of my close friends are beginning to start families of their own. I had a pregnant colleague from work who lovingly referred to her unborn child as a ‘parasite’. Recently, my sister gave birth to her first child, a healthy handsome young boy name Gabriel. Prior to his delivery, I was asked about the Zika virus: How is it spread? Should I be worried since I was bitten by a mosquito? Can I prevent myself from being infected with Zika? What is the treatment? These concerns are appropriate for any mother.

The Zika pandemic brought with it fears and misinformation. It is a disease that most people never heard of before, and became a sudden worldwide threat in 2014 when thousands of cases of microcephaly (baby’s head is smaller than expected) in Brazil. Unfortunately, no one knew much about the disease. Worried mothers would ask, “If I was in (insert country), should I be worried?” As I am listening to these concerns, I am reminded of the fear and paranoia of Ebola had in the United States, despite the problem being less of an issue for most Americans. Zika is currently a global issue, but there are other congenital infections that are more common and with harsher consequences than Zika. There are multiple types of these pathogens, but the most common ones are grouped together as TORCH (Toxoplasmosis, other diseases, Rubella, Cytomegalovirus, and Herpes). Those other diseases include Syphilis. Personally, I prefer the name STORCH, after learning from my friend who also had her second child recently, is the German word for ‘Stork’ and seemed quite appropriate for a group of microbugs that can affect a newborn.

There are a few reasons on why I am writing this article. The first is to bring awareness and to better educate expecting mothers or for those wishing to start a family. The second reason is selfishly for myself, as I want to further understand these infectious diseases at a deeper level and hopefully prepare me when I would eventually start my own family in the future. The third reason is to better educate health care professionals to teach their patients the risk and preventions.

Toxoplasmosis

A 20-year-old woman in Brazil gave birth to twins at 31 weeks’ gestational age [1]. During the neonatal period, the mother noticed one of the twins always appeared sluggish, with problems opening one of his eyes. Further examination of the right eye showed a whitish lesion. The infant also had a smaller head compared to its twin. CT showed the presence of calcifications in the brain. Toxopasma gondii was confirmed. The patient underwent 15 months of treatment with sulfadiazine, pyrimethamine and leucovorin. By the age of 7, the patient had an eye exam at school, and revealed impaired vision in the left eye and normal vision in the right.

In 1914, Dr. Castellani was the first to describe T. gondii-like parasite from a 14-year-old boy who died from a disease characterized by severe anemia, fever, and a large spleen [2]. By 1923, Josef Janku reported on an 11 month-old child who was admitted to the hospital after suffering from enormous increasing head size (hydrocephalus) [3]. The child later died and showed signs of chorioretinitis. On May 23, 1938, an infant girl in New York was delivered at full-term by Caesarean section. Three days after delivery, the child developed seizures and chorioretinitis was present in both eyes [4]. At one-month of age, the child died and upon autopsy, free and intracellular lesions were found in the brain and eyes. In 1939, three pathologists; Wolf, Cowen, and Paige, were the first to conclusively identify T. gondii as a cause of human disease [5].

Congenital toxoplasmosis occurs after the mother is infected during pregnancy from the protozoan parasite known as Toxoplasma gondii. Two studies in the 1970s both reported rates of approximately 10 per 10,000 live births, meaning an estimated 400-4,000 infants would be born each year with congenital toxoplasmosis [6]. The later the maternal infection, the lower the risk of any clinical manifestations, with most infections acquired during the third trimester often asymptomatic at birth.         

It is important to note the complex, but straightforward life cycle of this parasite [6]. Cats play a major role in how the disease is spread, with cats becoming infected after consuming creatures harboring the disease. It should be noted that the Toxoplasma parasite does not become infectious until one to five days after it is shed in cat’s feces. Humans can become infected by: eating undercooked meat, consuming food or water contaminated with cat feces, blood transfusions or organ transplantation, and transplacentally from the mother to the fetus. To prevent the risk of infection, maintaining good hygiene is key. It is best to avoid drinking untreated water and wear gloves when gardening during any contact with soil or sand. For pregnant cat owners, there are special precautions that must be considered: 1) feed cats only canned or dried commercial food or well-cooked table food, 2) keep cats indoors, 3) have someone else clean the litter box daily, 4) if no one else can clean the litter box, wear disposable gloves and wash hands with soap and water afterwards, 5) and do not adopt or handle stray cats, especially kittens.

The classic clinical manifestations for congenital toxoplasma gondii are: 1) Chorioretinitis, 2) Hydrocephalus, and 3) Intracranial Calcifications [6]. Other symptoms that can be present include: anemia, deafness, fever, growth retardation, large liver and spleen, low platelet counts, visual impairment, and learning disabilities/mental retardation. Premature infants with toxoplasmosis may develop CNS and ocular disease in the first three months of life. Although most infants infected in utero are born with no obvious signs of disease on routine examination, approximately 80% will develop visual or learning disabilities later in life.

Figure 2: Chorioretinitis

Figure 3: Hydrocephalus with increasing ventricle size.

Figure 4: Calcifications in the brain

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Syphilis

A premature female newborn at 31 weeks gestational age was brought into the neonatal intensive care unit (NICU) due to difficulty in breathing [7]. Her abdomen was distended and had a large liver and spleen. Multiple yellowish pustules and bullae were found on her face, trunk, arms, and legs. The diagnosis of congenital syphilis was made and both parents were tested for syphilis. The newborn was treated with penicillin G (IV) for 14 days. The skin lesions diminished after six weeks of treatment. Six months of follow up showed no evidence of recurrence.

Throughout history, this illness had multiple names: the French disease, the Spanish disease, the Dutch disease, the American disease, and so on [8]. In 1586, Guilleaume Rondelet described a newborn at birth covered by the pustules called morbus gallicus [9]. In Berlin of 1905, zoologist Fritz Schaudinn and dermatologist Erich Hoffmann had identified Spirochaeta pallida, and renamed within the same year as Treponema pallida, the main culprit behind syphilis [10].

The number of Congenital syphilis had increased in the United States during 2012 to 2014, from 334 to 458 cases (approximately 12 births per 100,000) [11]. By 2015, cases of syphilis infection had also increased. The number of stillbirths in 2014 was 25, with eight deaths within the first 30 days of delivery. Among those who were born in 2014 with the disease, 6.5% had one or more clinical signs: syphilitic rash, jaundice, and hepatosplenomegaly.               

Congenital syphilis can have a major impact towards the fetus [11]. The effects on the newborn is dependent on how long the mother had syphilis and if or when she got treatment for the infection. It is possible that the baby with Congenital syphilis will not have any symptoms at birth, but without treatment serious problems may develop, usually within the first few weeks, but can occur years later. Early signs and symptoms include maculopapular rash (reddening of the skin with small lumps) and desquamating erythema (redness, swelling, and shedding) of the palms, soles, and skin around the mouth and anus. Syphilitic pemphigus is when there is blistering, especially on the palms and soles. Congenital syphilis can also lead to the weakening or perforation of the nasal septum, that can lead to “Saddle nose.” Syphilitic rhinitis, known as “snuffles” is often found in these babies, with the mucus filled with the bacteria.

Figure 5: Skin lesions from Congenital syphilis. (Source: The New Zealand Medical Journal, Vol 120, No 1250)

Figure 6: Saddle Nose (Source: CDC)

Late onset of Congenital syphilis include a condition called Saber shin, which is a malformation of the lower limb and presents as the frontal bowing of the tibia (anteriorly-curved tibia bone) [11]. The Classic Hutchinson triad includes three manifestations: 1) Involvement of the teeth, with notched, peg-shaped incisors known as Hutchinson teeth, 2) Chronic inflammation and scarring of the cornea stroma (the layer between the outer and inner layers of the cornea) that leads to Interstitial keratitis, and 3) Sensory-neural hearing loss (SNHL) with deafness of the eight cranial nerve.

Figure 7: Saber shins, or osteoperiostitis of the tibia. (Source: CDC)

Figure 8: Hutchinson Teeth, notching of the upper incisors.

Figure 9: Interstitial keratitis, inflammation of the cornea.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Rubella

A full-term boy was delivered by cesarean section because of cardiac decelerations during labor, and presented with microcephaly and a petechial (tiny red dots) rash on the face, back, and upper arms [12]. A systolic heart murmur was heard. CT scans of the infant’s head showed small calcifications. About 6 months of age, the child had delays in attaining developmental milestones. The CDC confirmed the presence of Rubella when the infant was 12 months of age.

In 1941, Australian ophthalmologist Norman Gregg linked congenital cataracts to maternal rubella infections during pregnancy [13]. In 1964, Rubella (also known as “German Measles”) infected approximately 12.5 million Americans (6.5% of the population) [14]. This pandemic swept across Western Europe and the United States. The event provided the unfortunate opportunity to properly identify and define CRS. Despite the virus causing a mild illness, it is one of the few diseases which regularly causes birth defects when contracted by pregnant women. The risk for CRS is higher if maternal exposure occurs during the first trimester.

Based on the National Center for Immunization and Respiratory Disease and the National Congenital Rubella Registry, there had been an average of 2-3 cases of Congenital Rubella Syndrome (CRS) reported annually during 1998 to 2012 [15]. The decline since the mid-1970s was due significantly to an increased effort to vaccinate at risk and susceptible children and young adults, especially women. In 2004, Rubella in the United States was declared eliminated and cases occur mostly through international travel. 

Rubella initially begins in the respiratory tract and can spread when an infected person coughs or sneezes [15]. As the virus replicates, it can spread to other tissues in the body: skin, lymph nodes, joints, and especially the placenta and fetus. The exact mechanism on how the fetus is damaged is not fully understood.

The classic triad of symptoms for CRS are: 1) Sensorineural Deafness, 2) Vision impairment, and 3) Heart Defects [15]. Hearing loss is the most common issue, that occurs in approximately 58% of patients. Hearing impairment may include only one or both sides of the ears. If the hearing loss is one-sided, detection may go unnoticed.

Vision impairments occurs in approximately 43% of patents and include: cataracts, glaucoma, and pigmentary retinopathy (most common) [16]. The cataracts had been classically described as pearly and dense, with congenital glaucoma occurring less frequently. The retinopathy is not the results of an inflammatory response, but the disturbance of the growth in pigment portion of the eye, causing some to be hyperpigmented (too much color) or hypopigmented (less color), leading to a “salt and pepper” appearance.

Figure 11: Congenital heart defects due to Rubella infection.

50% of infants infected in the first 2 months of gestation will have the risk of congenital heart disease which includes: patent ductus arteriosus (PDA) and pulmonary artery stenosis [15].

In 1925, Dietrich first documented odd skin markings in newborns. During the American epidemic of Rubella, the term “blueberry muffin baby” was coined by pediatricians to describe the skin manifestations in newborns [17]. These children showed the presence of purplish discoloration under the skin (hemorrhagic purpuric eruptions).

Figure 12: Blueberry Muffin Baby in a newborn (Source: Dermatology Online Journal, 14(2))

Rubella can be prevented with MMR (Measles-Mumps-Rubella) vaccine [15]. CDC recommends children get two doses of MMR vaccine, starting with the first dose at 12 through 15 months of age, and the second dose at 4 through 6 years of age. Because of the severity for a pregnant mother and her baby, those who are not vaccinated against rubella is at risk of getting the disease. Women who are planning to become pregnant should check whether they are vaccinated before they get pregnant. Pregnant women should not get vaccinated. Because the vaccine contains an attenuated (weakened) live virus, pregnant women should wait after the delivery to get the vaccine. Those who are pregnant and believed to have contracted rubella should contact their health provider immediately.

Cytomegalovirus

A 33-year-old mother delivered a baby boy by caesarean section, due to intrauterine growth restriction (IUGR) [18]. The length and head circumference of the child was below the 0.4th percentile. He was noted to have multiple ecchymoses (bleeding under the skin) on the trunk and lower limbs at birth. The liver and spleen were enlarged. Ultrasound of the head showed multiple calcifications. Test for Cytomegalovirus (CMV) was positive for both the mother and baby. On follow up, the patient’s growth was retarded and his development was severely delayed. At 18 months, he developed seizures. He showed signs of deafness in both ears and was visually impaired.

In 1881, Dr. Hugo Ribbert studied the kidneys of a stillborn infant with syphilis [19]. Upon closer inspection, he described abnormal structures found inside the cells known as inclusion bodies. These inclusions were in the nucleus of the cell and was separated by a clear halo around the nuclear membrane. Over the years, inclusions were found not just inside the nucleus, but also outside within the cytoplasm of the cell. By 1950, Dr. Smith and Dr. Vellios determined that these inclusion bodies were specific to a source and majority of these cases occurred during the first 2 years of life, indicating that the infection may occur in utero [20]. By 1957, strains of a virus had been isolated by three different scientists. In 1960, Dr. Thomas H. Weller, a pediatrician, parasitologist and virologist, named the virus “cytomegalovirus” [21].

Figure 13: Various infected cells with inclusion bodies within the nucleus and cytoplasm and with a clear halo surrounding the nuclear membrane.

About one in every 200 deliveries are born with Congenital CMV infection, yet about one out of five of those infected will show the disease or have long-term health issues [22]. The virus is common and infects at various age groups. Once infected, the virus stays for life in the body and can run the risk of reactivation. Most people infected show no signs of symptoms or illness. The disease presents as fever, sore throat, fatigue, and swollen glands. It is spread through direct contact with urine or saliva, sexual contact, breast milk, and transfusions of infected blood.     

Figure 14: Infant with hepatosplenomegaly.

Figure 15: CT scan of head with the presence of periventricular calcifications.

Congenital CMV is the most frequent agent implicated in newborn infections and it can be the source of serious newborn disease [22]. Mothers can pass the virus to their baby during pregnancy. This can occur when a pregnant woman is infected for the first time, re-infected with a different viral strain, or a reactivation of a previous infection during pregnancy. Most babies who are infected with CMV show no signs or any health problems. These problems may develop later in the child’s life. It is also possible to cause a miscarriage during pregnancy. Signs of congenital CMV infection at birth include: being born too small for their gestational age, born with a small head (microcephaly), seizures, and problems with their liver, lung and spleen.

Long-term complications include chorioretinitis. Hearing loss may be identified only later in life. On a CT scan, the presence of periventricular calcification can be seen in severe cases.

For pregnant mothers, contact with saliva or urine of young children is a major cause of infection with CMV [22]. It is important to not share food, drinks, or utensils with children under six years of age. It also important to maintain proper hygiene such as washing hands after interacting with a child: changing diapers, feeding, or handling children’s toys.

Herpes Simplex Virus

A 20-year-old mother delivered a baby boy at 39 weeks with no complications [23]. 10 days after delivery, the boy had a fever and was brought to his primary care doctor. The mother denied any significant illnesses during her pregnancy and denied any history of exposure to herpes, as well as had no knowledge of any vaginal vesicular lesion. He was admitted to the hospital. Results from the patient’s CSF was positive for Herpes Simplex Virus (HSV). The patient was treated with Acyclovir, and at his 1-year well-child check-up, showed no developmental or neurologic issues.

The term “herpes” was used as early as the 4th century BC and referred to any “creeping” skin lesions. Genital herpes was first described in the literature by the French physician Jean Astruc in 1736 [24]. He examined Parisian commercial sex workers and was the first to document the description of genital herpes. In 1934, an Italian ophthalmologist named Dr. Natignani reported a case of an infant with acute keratoconjunctivitis, and found to also have cells with the characteristic inclusions bodies associated with herpes [25]. Almost a year later, Dr. Hass, an American pathologist, published his findings of an infant who died from a presumed bacterial sepsis, with HSV inclusion bodies found in the liver and adrenal glands [26].

Figure 16: Multinucleated giant cells caused by herpes simplex and herpes zoster viruses. (Source: John L. Bezzant, M.D.)

The frequency of neonatal herpes infection ranges from 8 to 60 per 100,000 with an estimated 1,500 new cases in the United States each year [11]. There are two types of herpes simplex virus, type 1 (HSV-1) and type 2 (HSV-2). Both viruses are transmitted across epithelial mucosal cells, as well as open skin wounds. The virus can migrate to nerve tissues where they persist in latent state and can reactivate and “flare up.” HSV-1 are mostly associated with oral infections and can be typically found in the trigeminal nerve ganglia, while HSV-2 are mostly associated with the genital infections and found in the lumbosacral nerve ganglia. 

The highest risk populations are those women with active herpetic lesions found during pregnancy [27]. Women with a history of genital tract herpes need to be instructed by their physicians on what they should do. The virus is transmitted to the infant during birth, with the highest risk in a primary infection acquired during pregnancy, compared with reactivation of previous infections.

There are three forms of neonatal herpes [28]. 1) Skin, Eyes, and Mouth (SEM) herpes, associated with skin lesions around those areas without the involvement of internal organs. 2) Involvement of the central nervous system (CNS) with signs of lethargy, respiratory distress, poor feeding, and fever. Long term issues could lead to developmental delays, blindness, or epilepsy. 3) Disseminated herpes infection is the most severe form of neonatal herpes. Mortality is about 85% if left untreated in newborns, and usually observed at 5 to 9 days of age. Signs include: jaundice, seizures, difficulty in breathing, irritability, and shock. It is associated with liver dysfunctions, pulmonary issues, and coagulopathy. Because the symptoms are nonspecific and resemble sepsis, early antiviral treatment with Acyclovir is often delayed.

Figure 17: (Left) Skin, Eyes and Mouth (SEM) Herpes. (Middle) Central Nervous System (CNS) Herpes. (Right) Disseminated Herpes with involvement of internal organs (Source: Journal of Perinatology, Vol. 22, Pages 86-88)

Zika Virus

A 25-year old woman became pregnant in early 2015 [29]. During her 13th week of gestation, she had high fever with severe musculoskeletal and eye pain with itchy rash all throughout her body. It was at this time her community had a ZIKV epidemic and infection with the Zika virus is highly suspected. Ultrasound at 14 and 20 weeks of gestation revealed normal fetal growth and anatomy. By the 29th week of gestation, ultrasound showed reduced fetal movement, and by the 32nd week of gestation, intrauterine growth retardation was confirmed. Structures of the brain showed multiple calcifications and was given a poor prognosis. Pregnancy was terminated at 32 weeks [30].

Figure 18: Numerous calcifications in the brain. (Source: University Medical Center of Ljublijana.)

Because of the ongoing spread of the virus, new countries are added on the growing list of areas where Zika is present [31]. To determine whether your area is at risk, please refer to your local public health facility. 44 states reported cases of pregnant women with Zika in 2016. One out of ten pregnant women confirmed with Zika had a fetus or baby with birth defects. Brain imaging is crucial to identify babies who appear healthy but have underling brain damage.

Figure 19: Aedes mosquito species.

April 1947, a virus was isolated from a rhesus monkey in the Zika Forest near Lake Victoria, Uganda [32]. Found in African and Asian Aedes species of mosquitoes, the virus was maintained in a cycle in monkeys, with humans as incidental hosts. Aedes mosquitoes are daytime biters (mostly at dusk and dawn) and prefer to breed in stagnant water (empty cans, old tires, bird baths, overgrown ditches, unmaintained swimming pools, open septic tanks, and sewage). These mosquitos also spread: Dengue, Yellow Fever, Chikungunya. Zika could also be transmitted through sexual contact, but insect-borne is its main form of transmission.  In 1952 researchers injected Zika virus into the stomachs of mice and subsequently found traces of the virus in their brains [33]. Another study, in 1971, showed that when injected directly into the brain, the virus can proliferate and infect both neurons and glial cells [34]. Further studies are required to determine the exact pathophysiology on the fetus.

Figure 20: Range of Microcephaly Severity (Source: CDC).

Symptoms for Zika is self-limiting and consist of fever, maculopapular rash, joint pain, conjunctivitis, muscle pain, and headache [31]. Due to the mild signs it presents, it is considered the weaker of the diseases compared to its other cousins, Chinkungunya and Dengue. Congenital Zika syndrome is described as severe microcephaly, decrease brain tissue, damage to the back of the eye, limited range in motion of the joints, and restricted movement due to increase muscle tone after birth. There have been several cases of Guillain-Barre Syndrome (GBS) associated with Zika infection. GBS is a problem with the nervous system that causes muscle weakness, loss of reflexes, and numbness or tingling in the arms, legs, face, and other parts of the body that can cause paralysis.

There is no specific treatment for Zika virus infection, with management consisting mostly of rest and drinking plenty of fluids [31]. Acetaminophen should be used to relieve fever and pain. Aspirin and nonsteroidal anti-inflammatory (NSAIDS) should be avoided until dengue had been ruled out to prevent the risk of hemorrhage. Aspirin should be avoided in children to avoid Reye Syndrome, a condition that leads to altered mental status and vomiting. The main prevention against Zika is to prevent getting bitten by mosquitoes. This would include covering up with long-sleeved shirts and pants, use only EPA-registered insect repellent with one of the following active ingredients: DEET, Picaridin, Oil of Lemon Eucalyptus (OLE) or Para-methane-diol (PMD), or IR3535. Remove stagnant pools of water in urban areas to get rid of breeding sites for mosquitoes. For mothers who are pregnant, they should consider postponing travel to any area where Zika virus transmission is ongoing. If they must travel to one of these areas, they should strictly follow steps to prevent mosquito bites during the trip.

Final Thoughts

According to the American Congress of Obstetricians and Gynecologists (ACOG), early pregnancy loss is common and occurs in about 10% of known pregnancies, with structural birth defects in 1 in every 33 babies in the United States. In the process of making new life, the machinery at the cellular level is awe-inspiring. With so much that could go wrong at every step of the way, it is a miracle that everything goes right so often. I would like to say “cheers!” to my mother, my sister, to all my family and friends who had or will give birth. I am sure most mothers would look at their child and think, “Wow, I made you.”

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