Acral Manifestations Associated with Various Infections

Acral manifestations are common in several infectious diseases. They may be present as distinctive lesions or involve the entire hand or foot. The palmar and plantar areas may be the only sites involved or other body areas/organs may also be involved.

Diagnosing the underlying disease is challenging even for experienced clinicians. Therefore, the diagnostic approach should include a careful clinical history (including age, season, drug use, flares, time of onset and place of onset, prodromal phase, fever, other complaints or symptoms, course, family history). and a complete physical examination (including skin and mucocutaneous areas or associated abnormal findings) and, if necessary, additional laboratory tests and technical investigations.

A concise differential diagnosis of infectious and non-infectious disorders with acral manifestations is outlined in Table 1.

2.1 Viral

> 2.1.1 COVID-19

Many skin manifestations have been attributed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) since the beginning of the Covid-19 pandemic, some of them preferentially related to the extremities.1 They can present as bilateral symmetrical redness of the extremities. palms involving the thenar region, the hypothenar region, and the fingertips.2 More common are chilblain-like acral lesions of the toes, commonly referred to as “COVID toes . ”

Erythema and edema of the affected areas often cause pain/burning sensations or pruritus. Multiple round lesions usually occur simultaneously and range from a few millimeters to centimeters in size. Although they sometimes affect all the toes, they show a clear demarcation at the metatarsophalangeal level.3 They often evolve with superficial centrifugal peeling.2,4 These pernio-type lesions occur mainly on the feet of young patients with mild general symptoms of COVID-19. 19.5,6

Apart from erythema pernio, a morbilliform, urticarial, maculopapular or pityriasis rosea-like acral rash and a papulosquamous and vesicular rash have also been described.1,2,6,7 In many cases, these manifestations were present before IgM seroconversion. anti-SARS-CoV-2 could be demonstrated.1,5 Most of these skin lesions resolve spontaneously within 1 to 4 weeks.1,4 Detection of the underlying cause is recommended if these lesions do not resolve within 30 days.5,8

The acral area is also the preferred site for exudative erythema multiforme, which has been described not only in association with infection but also as an adverse event of COVID vaccination. Although it has been observed in adults and adolescents, pediatric dermatologists should take it into account due to the increase in vaccination of younger children.9,10

Loss of taste or smell, and respiratory symptoms ranging from dry cough to shortness of breath, have been reported as accompanying symptoms.

In a minority of cases, SARS-CoV-2 can cause multisystem inflammatory syndrome in children (MIS-C). Fever is a key symptom, often accompanied by gastrointestinal, cardiovascular, and respiratory manifestations. In addition, a variety of rashes can be observed with frequent palmoplantar involvement and marked periorbital as well as malar edema and erythema.11,12 Although at first it usually has a benign presentation, the majority of patients with MIS-C show severe physiological deterioration that requires intensive care and supportive therapy.4,12-14

To date, no treatment has been shown to be effective for these skin lesions. Supportive treatment and expectant management appear to be the most appropriate approaches. However, if MIS-C is suspected, treatment with intravenous immunoglobulin (IVIg) with or without IV methylprednisolone (depending on the presence of shock or disease with organ involvement) should be initiated promptly.14

> 2.1.2 Hand-foot-mouth disease

Hand-foot-mouth disease (HFMD) is a common enteroviral disease caused primarily by coxsackievirus A6 and A16 (less commonly coxsackievirus A2, A5, A9, A10, B2, B3, B5 and enterovirus 71), typically affecting children under five years of age during the latter part of summer and fall.15,16

Characteristic deep, oval, gray blisters or vesicles of various sizes (2-8 mm) are seen on the palmoplantar surfaces in the classic form of HFMD. They are frequently accompanied by similar lesions on the dorsal aspect and sides of the fingers. Rarely, crusted, hemorrhagic, and confluent lesions may also be seen on the extremities.

Compared with the classic presentation, atypical coxsackie A6-mediated EMPB is characterized by a more widespread distribution, a polymorphic pattern, and altered general status. Infection with Coxsackie virus A6 in atopic patients can cause “eczema coxsackium.”17 Onychomadesis and desquamation may occur in the convalescent phase.

The exanthema of HFMD is often preceded by a prodromal stage of subfebrile temperatures, loss of appetite, odynophagia, and abdominal pain.15 Painful vesicles and erosions on the oral mucosa and tongue 1 to 2 days after the onset of fever are strongly associated with with the disease but are not always present.15,16,18 The putative diagnosis can be confirmed by directly detecting the virus from blister material, nasopharyngeal secretions, cerebrospinal fluid (CSF), or blood using PCR or biopsy specimens.18

The disease is self-limiting in 7 to 10 days,15 but patients with humoral and combined immunodeficiencies may develop persistent central nervous system infections, a dermatomyositis-like syndrome, or disseminated infection. Treatment is usually supportive. Antiviral or immunomodulatory therapy may be an option for chronic enterovirus meningoencephalitis in immunocompromised patients.19

> 2.1.3 Herpes simplex virus

Herpes simplex virus (HSV) is one of the most prevalent viruses due to its ease of transmission. The virus is acquired from a subclinical or symptomatic source through contact with herpetic lesions, mucous secretions, or skin containing HSV.20,21 After adhesion and entry into epithelial cells, the virus is transported to the sensory ganglia by retrograde transport, establishing a lifelong latent infection.22 Infections are most frequently acquired during intimate contact, posing a significant risk to newborns during childbirth, children in day care centers, sexually active adolescents, and athletes involved in contact sports.20

Children usually develop clinical illness 2 to 12 days after exposure, with gingivostomatitis or oral blisters and systemic symptoms including fever, malaise, and headache. The infection may then remain limited to oral lesions or progress to systemic involvement, with alteration of the central nervous system.20,23

The most common acral skin manifestation is “herpetic whitlow,” after autoinoculation of the virus through a wound in the skin barrier. The clinical picture consists of a sensation of pain or burning followed by local edema, erythema, and one or more small, tender inflammatory vesicles.24 Other less common presentations are palmar pustules and bullae.25,26

If left untreated, these infections gradually heal in 2 to 3 weeks but may recur.27 Antiviral therapy started early during primary HSV infection or outbreaks leads to faster healing of lesions, decreased pain, and shorter duration. of fever.28

> 2.1.4 Human parechovirus-3

Human Parechovirus-3 (HPeV-3) infection generally presents in neonates and young infants as a sepsis-like condition with fever, tachycardia, tachypnea, and rash.29 Palmoplantar erythema characteristically appears on the second or third day after the onset of fever and disappears simultaneously in 2 to 3 days with defervescence. No traces of pigmentation or scars are observed.29,30

This erythematous rash is suggestive but not pathognomonic of HPeV infection. Confirmation of HPeV-3 infection is necessary and possible by PCR analysis of serum and CSF.29 HPeV-3 infection may be associated with neurological morbidity (e.g., meningoencephalitis or any form of white matter injury) in neonates. , but prediction of neurological outcome remains difficult. A possible association with hyperferritinemia has been reported.30

There is no specific therapy available for HPeV infections. Hand hygiene

and contact precautions are essential to limit the spread of HPeV within families and institutions.

> 2.1.5 Orf

Orf (or contagious ecthyma) is a zoonotic viral skin infection caused by a parapox virus. It is contracted through contact with infected sheep and goats. The Orf nodule occurs mainly as a solitary lesion on the fingers, hands, or forearms.31,32 It usually presents 3 to 7 days after inoculation, beginning as a small firm red or reddish-blue lump, which evolves into a vesicle, pustule, or hemorrhagic blister, scab and finally spontaneous healing without scarring within 6-8 weeks.31

Reported complications are bacterial superinfection, lymphangitis, lymphadenopathy, erythema multiforme, and bullous pemphigoid.31 Diagnosis is generally based on history and physical examination. If in doubt, a skin biopsy or molecular testing of the affected skin may be performed.33 Treatment is symptomatic, with antibiotics to treat secondary bacterial infections.

> 2.1.6 Papulopurpuric syndrome in gloves and stockings (PPGM)

SPPGM is a distinctive manifestation related to human parvovirus B19, mainly affecting adolescents and young adults. However, it has also been reported after CMV, EBV or mycoplasma infections, and after ingestion of various drugs.15,16,34-36

SPPGM begins with edema and erythema of the hands and feet, evolving to a monomorphic eruption of purpuric papules and macules with marked demarcation on the wrists and ankles. An enanthema with oral vesicles, erosions and ulcers can also be seen.15,16,34-36

SPPGM is often preceded by prodromal symptoms, including low-grade or moderate fever, lymphadenopathy, myalgias, arthralgias, and fatigue.15,16,34-36 Treatment is symptomatic. Spontaneous resolution occurs within 1 to 2 weeks, often with palmar and plantar peeling, but without long-term sequelae.

> 2.1.7 Other viruses

Diffuse palmoplantar erythema has recently been observed in the context of adenovirus and respiratory syncytial virus (RSV) infections. Unlike SPPGM, lesions in both conditions did not show progression to purpuric macules and papules but remained shiny and erythematous before showing spontaneous resolution without desquamation. The skin lesions were not always accompanied by other traditional symptoms of these common viral infections.

Viral tests can be performed to confirm the etiology. In general, reassurance about the benign, self-limiting course of symptoms is most important.

2.2 Bacterial

> 2.2.1 Infective endocarditis

Infective endocarditis (IE) is an infection caused by bacteria (staphylococci, streptococci, gram-negative bacilli) that enter the bloodstream and settle in the pericardium or a heart valve, altering cardiac function and may result in distal embolization, which originates from the formation of thrombi from vegetations. Acute IE usually begins with high fever, chills, night sweats, joint and muscle pain, persistent cough, or edema and ascites. Chronic IE can also present with weight loss and anemia.37

Painless erythematous or violaceous macules on the palms of the hands and soles of the feet are called Janeway lesions. These may present with or without splinter hemorrhages: reddish-brown linear striae that run vertically under the distal portion of the nails.38 Janeway lesions and splinter hemorrhages are rare in neonates with endocarditis.37

The modified Duke Criteria can be used in the diagnosis of IE.

Multiple blood cultures should be obtained from patients with unexplained fever and a pathological heart murmur, a history of cardiac disease, or previous endocarditis.39

While awaiting confirmation by blood cultures, empiric parenteral coverage against staphylococci and streptococci with penicillin/ampicillin plus gentamicin can be initiated.40

> 2.2.2 Gonococcemia

Neisseria gonorrheae is a highly infectious large negative aerobic diplococcus that mainly affects the urogenital, anorectal or pharyngeal mucosa. Neonatal infection results from exposure to infected cervical secretions during childbirth. In preadolescent children, gonococcal infection is probably indicative of sexual abuse. Sepsis, meningitis, arthritis and conjunctivitis are the most serious complications.41

Skin lesions related to gonococcal infection may occur by direct inoculation of the mucosa or by dissemination of the disease.41,42 Disseminated gonococcal infection (DGI) is subdivided into two clinical syndromes: tenosynovitis-dermatitis syndrome (STD) and a of septic arthritis (SAS) without associated skin lesions.

STD usually begins in the first 2 to 3 days with an association of migratory arthralgia, distal tenosynovitis, and dermatitis. Dermatitis occurs mainly on the dorsal surface of the distal extremities near the joints and, less frequently, on the trunk, face, scalp, and oral mucosa. The lesions are typically few in number and occur in one or more groups, often beginning as punctate petechial macules and progressing to papules, vesiculopustules, and blisters, which may undergo necrosis or hemorrhage.42

Gonorrhea is documented by Gram stain of a swab showing diplococci

Gram negative, with the highest sensitivity in urethral, ​​pharyngeal and cervical samples. Cultures of skin lesions in disseminated gonococcal infections are usually negative.41 Untreated dermal lesions usually heal without scarring after 4 to 6 days.42 However, prevention of further dissemination by initiating treatment with ceftriaxone is essential to avoid systemic complications.43

> 2.2.3 Meningococcemia

Neisseria meningitidis is a large negative aerobic diplococcus resident in the upper respiratory tract. It is transmitted via the respiratory route through aerosol droplets or secretions from the nasopharynx.44 The most common clinical presentations of meningococcal disease are meningitis and meningococcemia. An acute upper or lower respiratory tract infection often precedes systemic invasion. Early symptoms resemble those of a viral illness and include chills, myalgia, nausea, and headache. Most patients develop skin manifestations.44,45

Petechiae usually appear first on the ankles, wrists, and armpits. They can consequently involve any part of the body, but generally spare the head, palms of the hands and soles of the feet. Initially, the lesions may be urticarial. Other less common skin lesions are macular or maculopapular rashes. The classic clinical features of meningococcal disease (e.g., hemorrhagic rash, meningism, and altered consciousness) often appear later in the course of the disease.44

Rarely, N. meningitidis can cause sepsis of at least a week’s duration without meningeal symptoms. This entity is called chronic meningococcemia and is characterized by persistent or intermittent fever, frontal headaches, migratory arthralgia and recurrent or persistent rash that can be maculopapular (47.6%), nodular (13.1%), petechial (11.9%). ) or polymorphic (27.4%). Between febrile episodes, the patient is usually asymptomatic.46

A positive blood culture will ultimately confirm the diagnosis. Obtaining this culture should not delay empirical coverage with Penicillin G as rapid deterioration may occur.45,47 Chemoprophylaxis is recommended for high-risk contacts of patients with invasive meningococcal disease.47

> 2.2.4 Pseudomonas hot foot syndrome

This syndrome can be considered a subtype of “hot tub folliculitis” with lesions limited to the feet. It can occur after use of hot tubs, swimming pools, jacuzzis, and saunas.48 Pseudomonas aeruginosa can enter the skin through hair follicles or skin abrasions. A high pH and low chlorine levels predispose to the multiplication of P. aeruginosa . In addition, the abrasiveness of the floor of swimming pools or bathtubs facilitates the intrusion of the stratum corneum by bacterial organisms.

Affected children develop lesions on the soles of the feet and/or palms of the hands 8-48 hours after exposure. These lesions manifest as tender, painful erythematous plaques with papules, papulopustules, or pruritic nodules.48,49 Occasionally, a concomitant urticarial rash appears on the trunk and extremities. In addition to skin lesions, there may be discomfort with low-grade fever. After contact with contaminated water, P. aeruginosa can also cause otitis externa and conjunctivitis.50

Skin lesions due to externally inoculated Pseudomonas aeruginosa infection are generally self-limiting.48,50 However, treatment with fluoroquinolones should be initiated if concomitant chronic suppurative otitis media or severe external otitis is observed. Prevention consists of correct maintenance and chlorination of swimming pools, jacuzzis, whirlpools and spas.48

> 2.2.5 Rocky Mountain spotted fever

Rocky Mountain spotted fever (RMSF) is a rare and underrecognized condition caused by Rickettsia rickettsii , an obligate intracellular bacterium spread by infected ticks.

The disease has been reported throughout the United States and throughout North and South America.51,52 RMSF is characterized by the sudden onset of fever (usually above 38.9°C), significant malaise, and headache. intense, it is usually accompanied by myalgia, anorexia, nausea, vomiting, abdominal pain and photophobia.51,52

During the early phase, RMSF can be misdiagnosed as a viral disease and RMSF-specific laboratory tests often lack additional value. Treatment should never be delayed while waiting for laboratory confirmation. Skin lesions are present in 80%-95% of patients and are therefore essential for diagnosis.53

The rash characteristically appears 2 to 5 days after the onset of fever with small (1 to 5 mm in diameter) blanching erythematous macules initially on the wrists and ankles, with subsequent centrifugal progression to the palms and soles in most cases. , then extending to the arms, legs and trunk.51-53 Other skin manifestations include an erythema migrans-type rash and post-inflammatory hyperpigmentation.51,52

Recommended treatment with doxycycline reduces mortality from RMSF to 5%. Without treatment, the mortality rate remains at 25% and patients may experience moderate or severe disease with pulmonary, hepatic, renal, neurological, and ocular manifestations that complicate the disease.51,54

> 2.2.6 Syphilis

Congenital syphilis is caused by Treponema pallidum that crosses the placenta to the fetus from 14 weeks of gestation.

Mucocutaneous involvement due to early congenital syphilis may be present at birth or develop during the first weeks of life. The hands and feet are the most affected by macular lesions that evolve into small coppery maculopapular lesions.

Petechial lesions may be seen if severe thrombocytopenia is present. Peeling and crusting occur during the first 3 weeks after birth.55,56 After the first 2 to 3 months, the perioral and perineal areas may be affected by warty or flat lesions, called condylomata. tin or flat, resulting in deep cracks.55

If left untreated, signs of late congenital syphilis usually appear after 2 years, but may appear up to 2 decades later.55,57 Recommended treatment in infants and children depends on disease progression.57

> 2.2.7 Tuberculous dactylitis

Extrapulmonary spread of Mycobacterium tuberculosis from an underlying tuberculous focus in the lymph nodes or bones can lead to secondary involvement of the skin. Tuberculous involvement of the small tubular bones of the hands and feet, also known as tuberculous dactylitis, is a rare presentation of bone tuberculosis (TB).58

Tuberculous dactylitis presents as a painless inflammation of the finger of a few months of evolution, most frequently affecting the proximal phalanx of the index and middle fingers. The bones of the hands are more frequently affected than the bones of the feet.59

Plain radiography is the best source of investigation for evaluation and follow-up, although there are no pathognomonic radiographic findings. The diagnosis of bone TB should be considered in patients with focal bone or joint anomalies and with a chest x-ray compatible with old or active TB.60

With adequate anti-tuberculosis treatment, complete healing of the affected bone with normal contour can be expected in most cases within 3 years.59

2.3 Fungal

> 2.3.1 Tinea pedis and manuum

Dermatophytes can be transmitted through floors, swimming pools, or homes and can be promoted by occlusive footwear.61 Dermatophytoses can be subdivided into superficial, cutaneous, and subcutaneous mycoses. Systemic mycoses due to primary pathogens usually originate in the lungs and can spread to other organ systems.

A moccasin-like presentation of tinea pedis is often caused by the genus Trichophyton and presents as dry, scaly, or hyperkeratotic plaques with mild erythema on the plantar and lateral surfaces of the feet.61 Painful or pruritic plaques may occur, along with ulceration, erosion and vesiculobullous lesions. There may be simultaneous involvement of the hand. Cellulitis or impetiginization suggests bacterial superinfection.61,62 A recent review by Kutlubay et al provides an extensive overview of these superficial fungal diseases.63

Aside from proper foot hygiene (including keeping feet dry and cool, gently cleaning, and avoiding occlusive footwear64), several over-the-counter and prescription topical antifungal therapies are available to treat mild cases of tinea pedis.65 If the infection is severe, chronic or refractory to topical treatment, oral therapy with fluconazole may be indicated.

> 2.3.2 Systemic candidiasis

Candida species are considered normal flora of the human gastrointestinal and genitourinary tract. However, an inadequate host immune response can cause systemic disease.

Congenital cutaneous candidiasis is the result of Candida infection in the womb or during childbirth. The affected infant typically presents with a diffuse skin rash at birth or within the first day of life. This rash consists of extensive erythematous papules and plaques that evolve into pustules and vesicles or blisters, and finally, peeling. The palms of the hands and soles of the feet are most affected, but any area of ​​the body can be involved.66,67

Very low birth weight newborns may present with a burn-like dermatitis within the first three days of life, with bright red patches followed by peeling.68

Invasive fungal dermatitis may also occur in very low birth weight infants within the first 2 weeks of life due to the impaired barrier function of their skin.69 These infants present with macular, papular, vesicular, or pustular acral or intertriginous lesions. These lesions can evolve into erosive lesions with crusting that affect the entire abdomen or back.

Blood cultures positive for Candida should prompt the search for the source and elimination if possible. Additionally, samples of skin lesions can be obtained for laboratory identification. It is also recommended to perform urine culture and culture of cerebrospinal fluid.

Neonatal systemic candidiasis requires aggressive and prolonged treatment until Candida species are cleared from the bloodstream and signs and symptoms attributable to candidemia have resolved.70

2.4 Miscellaneous

> 2.4.1 Kawasaki disease

Kawasaki disease (KD) is an acute febrile inflammatory disorder triggered by different infectious agents in genetically predisposed children, particularly those under 5 years of age.71

During the acute phase, erythema of the palms of the hands and soles of the feet is frequently observed. It may be accompanied by a firm and sometimes painful induration in the same areas. Peeling of the fingers and toes may appear within 2-3 weeks after the onset of fever (subacute phase). This usually begins in the periungual region and may spread to involve the entire palms and soles. Onychomadesis or Beau’s lines can occur about 1 to 2 months after the onset of fever (convalescent phase).71,72

High, stabbing and remitting fever, maculopapular or scarlatiniform rash, bilateral conjunctivitis, oral lesions and cervical lymphadenopathy complete the clinical picture. Diagnosis is often delayed in children with atypical KD, including in apparently afebrile children who have other findings consistent with KD and children with high fever ≥5 days with symptoms not usually seen in KD.73

Treatment with intravenous immunoglobulin G (IVIg) and aspirin should be initiated as soon as the criteria for classic or incomplete KD are met and when alternative diagnoses are unlikely or excluded.71,74 This early treatment has reduced acquired heart disease ( (e.g., dilations and aneurysms of the coronary arteries) associated with KD.71

> 2.4.2 Neutrophilic eccrine hidradenitis

Neutrophilic eccrine hidradenitis (HEN) is a form of inflammatory hidradenitis that results from the aggregation of neutrophils around the eccrine glands, which are highly concentrated on the palmar surface of the hands, fingers, and soles. HEN has been reported most frequently in patients receiving chemotherapy for cancer. Cancer itself, medications, and various infections such as adenovirus,75 Staphylococcus aureus , or Mycobacterium species76 can also cause HEN.

This invasion of neutrophils causes the progressive development of papules, nodules or erythematous plaques of variable size in a symmetrical distribution. Pigmented and purpuric lesions have also been reported.76 Rarely, HEN may involve the upper trunk, extremities, and face, particularly the periorbital areas. The groins or armpits are usually spared. Oral lesions are not seen unless they are related to underlying viral or bacterial infection.76

It may be associated with hematologic malignancies, especially acute myeloid leukemia. An association with chronic lymphocytic leukemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma has also been reported.76,77

These underlying diseases must be excluded or documented through very specific work. HEN itself is self-limiting with spontaneous resolution within 1 to 2 weeks in most cases.

As shown, acral manifestations of infectious disorders can be very subtle or very pronounced. Therefore, its occurrence should always encourage careful history-taking, a good clinical examination, and, if necessary, technical and laboratory investigations to determine the underlying disease.

Table 1. Differential diagnosis of acral manifestations associated with infection.

Acral manifestations are common in several infectious diseases, either as distinctive lesions or involving the entire hand or foot, and may be accompanied by involvement of other body areas.

Diagnosis of the underlying disease may be clear in some cases and challenging even for experienced physicians in others. Therefore, in the presence of these manifestations, the diagnostic approach should include a careful clinical history, a complete physical examination and, if necessary, additional laboratory tests and technical investigations to determine the underlying disease that causes them and the treatment. according to the case.