PULMONARY COMPLICATION OF SICKLE CELL ANAEMIA

Sickle cell disease (SCD) encompasses a group of hemoglobinopathies characterized by a single amino acid substitution in the beta globin chain. Hemoglobin S results from the substitution of a valine for glutamic acid as the sixth amino acid of the beta globin chain. The resulting hemoglobin tetramer (alpha2/betaS2) is poorly soluble when deoxygenated. This deoxygenated hemoglobin polymerizes into sheets of elongated rope-like fibers, causing a marked decrease in red cell deformability and distortion of the cell into the classic crescent or sickle shape. The most frequently occurring form of SCD is sickle cell anemia (HbSS).


Acute and chronic pulmonary complications occur frequently in patients with SCD, and represent the most common cause of death from SCD in adult.The common pulmonary complications are:

1. Infection
2. Embolic phenomena due to bone marrow infarction and fat emboli
3. Infarction caused by in-situ thrombosis
4. Rib and sternal infarctions
5. Pulmonary edema

Acute chest syndrome — The acute chest syndrome (ACS) is the most common form of acute pulmonary disease in patients with SCD. Signs and symptoms are

• Presence of a new pulmonary infiltrate
• Chest pain
• Temperature >38.5ºC
• Tachypnea, wheezing, or cough

Etiology of ACS is unclear.
Unknown cause — 46 %
Pulmonary infarction — 16 %
Fat embolism, with or without infection — 9 %
Chlamydophila (formerly Chlamydia) pneumoniae infection — 7 %
Mycoplasma pneumoniae infection — 7 %
Viral infection — 6 %
Mixed infections — 4 %
Other pathogens — 1%
Clinicl findings
following symptoms were present at the time of diagnosis of ACS
Fever — 80 %
Cough — 62 %
Tachypnea — 45 %
Chest pain — 44 %
Shortness of breath — 41 %
Arm and leg pain — 37 %
Abdominal pain — 35%
Rib or sternal pain — 21 %
Wheezing — 13 %
Management — The acute treatment of ACS is primarily supportive and is based upon the potential etiology.

Pneumonia — Patients with SCD are predisposed to develop pneumonia due to impaired host defenses, including loss of antibody protection (in the setting of auto-splenectomy), altered phagocytic function, and defective opsonization
Fat and bone marrow embolism — Bone marrow infarction resulting from
microvascular occlusion is the probable pathogenic mechanism common to the initiation of both fat and bone marrow embolism in patients with SCD  . Patients with SCD and pulmonary fat embolism (PFE) frequently have mental status changes, thrombocytopenia, falling hematocrit, and severe hypoxemia, a clinical presentation similar to that in patients in whom PFE develops following the fracture of long bones
Treatment options
Exchange transfusion
Plasma infusions
Glucocorticoids

Venous thromboembolism — Autopsy data of the lungs of patients with SCD reveal fibrin thromboembolism in larger arteries with or without infarction, and extensive thrombosis in smaller arteries

Sickle cell chronic lung disease — SCCLD may begin to develop as early as the second decade of life. Pulmonary dysfunction rapidly progresses, with death occurring within seven years of diagnosis Patients characteristically progress through four clinical stages based upon physiologic and radiographic data and symptoms
Stage 1 - recurrent chest pain and cough, mild reductions in forced vital
capacity (FVC) and total lung capacity (TLC), normal oxygen saturation,
and near normal chest radiographs with slightly increased interstitial
markings.
Stage 2 - greater pain than stage 1, moderate reductions in FVC and
TLC, normal oxygen saturation, and diffuse interstitial fibrosis (all lobes
on chest radiograph).
Stage 3 - severe, crushing chest pain, hypoxemia during stable periods
(PO2 approximately 70 mmHg), severe reductions in FVC and TLC, and
pulmonary fibrosis on chest imaging.
Stage 4 - prolonged chest pain, fixed dyspnea, hypoxemia at rest,
severe pulmonary fibrosis on chest radiograph, and elevated pulmonary
artery pressure at rest

Obstructive sleep apnea — Upper airway obstruction during sleep due to adenoid and tonsillar enlargement has been found in up to one-third of children with SCD

Alterations in baseline pulmonary function —M any different parameters of
pulmonary function are altered in patients with sickle cell lung disease. As examples:
Total lung capacity and vital capacity may be reduced
Even when corrected for anemia, the diffusing capacity for carbonmonoxide (DLCO) is abnormally low
Arterial oxygen saturation (SaO2) is reduced
The alveolar-arterial difference is widened both at rest and with exercise
Mild to moderate airflow obstruction may be present, particularly among patients with recurrent episodes of acute chest syndrome

pulmonary hypertension in patients with SCD is 20 to 40 percent

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EORTC/MSG Consensus Revised definitions on fungal infection

Proven invasive fungal diseases

Deep tissue disease

Moulds[1]

Histopathologic, cytopathologic, or direct microscopic examination[2] of a needle aspiration or biopsy specimen showing hyphal forms with evidence of associated tissue damage (either microscopically or as an infiltrate or lesion by imaging)[3]

OR

Recovery of a mould by culture from a sample obtained by a sterile procedure from a normally sterile and clinically or radiologically abnormal site consistent with an infectious disease process, excluding BAL, cranial sinus cavity, and urine.

Yeasts

Histopathologic or cytopathologic examination² of a needle aspiration or biopsy specimen from a normally sterile site excluding mucous membranes showing yeast cells (Candida species may also show pseudohyphae or true hyphae)

OR

Recovery of a yeast by culture from a sample obtained by a sterile procedure (including a freshly (<24h) placed drain) from a normally sterile and clinically or radiologically abnormal site consistent with an infectious disease process,

Fungemia

Moulds

Blood culture that yields a mould e.g. Fusarium spp. in the context of a compatible infectious disease process[4].

Yeasts

Blood culture that yields yeast (e.g. Candida species) or yeast-like fungi (e.g. Trichosporon spp.)

Endemic fungal disease[5]

Disseminated and/or pulmonary[6] disease

Must be proven by recovery in culture from a specimen obtained from the affected site, in host with a temporally related illness consistent with a fungal infectious disease process;

OR

if culture is sterile or not obtained, histopathologic or direct microscopic demonstration of appropriate morphological forms is considered adequate for dimorphic fungi having truly distinctive appearance.[7]

OR

Positive blood culture

In the case of histoplasmosis a diagnosis of disseminated disease may be established by a positive Histoplasma antigen test[8] on CSF, urine or serum by EIA, or the presence of characteristic intracellular yeast forms in a peripheral blood smear or in bone marrow.

Or in the case of coccidioidomycosis a diagnosis of disseminated disease may be established by demonstration of coccidioidal antibody⁹ in CSF, or a 2-dilution rise measured in two consecutive blood samples tested concurrently in the setting of a temporally related infectious disease process.

Cryptococcosis

Probable invasive fungal disease

Defined by at least

a) one host criterion

AND

b) one clinical criterion

AND

c) one microbiological criterion

Possible invasive fungal disease[9]

Defined by at least

a) one host criterion

AND

b) one clinical criterion

BUT

c) no microbiological criterion

Host factors

Host factors are not synonymous with risk factors and are characteristics by which individuals predisposed to invasive fungal diseases can be recognized. They are intended primarily to apply to patients treated for malignant disease and to recipients of allogeneic hematopoietic stem cell and solid organ transplant. These host factors are also applicable to those receiving corticosteroids and other T-cell suppressants as well as those with primary immune deficiencies

1)   Recent history of neutropenia (< 0.5 x 10⁹/L {<500 neutrophils/mm³} for >10 days) temporally related to the onset of fungal disease or ongoing neutropenia

2)   Receipt of an allogeneic stem cell transplant

3)   Prolonged use of corticosteroids (excluding patients with ABPA) at an average minimum dose of 0.3 mg/kg/day prednisone equivalent for > 3 weeks

4)   Treatment with other recognized T-cell immune suppressants such as ciclosporin, TNF-a blockers, specific monoclonal antibodies alemtuzumab, nucleoside analogues during the past 90 days

5)   Inherited severe immunodeficiency (e.g., chronic granulomatous disease, severe combined immunodeficiency)

Clinical criteria

Must be consistent with the microbiological findings, if any, temporally related to current episode and other potential causes must have been eliminated

Lower respiratory tract fungal disease

A) the presence of one of the following “specific” imaging signs on CT:-

·         Well defined nodule(s) with or without a halo sign

·         Wedge-shaped infiltrate

·         Air crescent sign

·         Cavity

B) the presence of a new non-specific focal infiltrate

PLUS at least one of the following[10]:-

Pleural rub

Pleural pain

Hemoptysis

Tracheobronchitis

Tracheobronchial ulceration, nodule, pseudomembrane, plaque or eschar seen on bronchoscopy

Sinonasal infection

Imaging showing sinusitis

PLUS

at least one of the following:-

Acute localized Pain (including pain radiating to eye)

Nasal ulcer, black eschar

extension from the paranasal sinus across bony barriers, including into the orbit

Endophthalmitis

as determined by ophthalmologic examination

CNS infection

at least one of the following:-

Focal lesions on imaging

Meningeal enhancement on MRI or CT

Chronic disseminated candidiasis

Small, peripheral, target like abscesses (new nodular filling defects, bull’s-eye lesions) in liver and/or spleen

Microbiological Criteria

Cytology, direct microscopy or culture:

1.      sputum, BAL and bronchial brush samples demonstrating the presence of fungal elements either by recovery by culture of a mould (e.g. Aspergillus spp., Fusarium spp., Zygomycetes, Scedosporium spp.) or detection by cytology or direct microscopy of hyphal forms

2.      sinus aspirate: recovery by culture of moulds from or detection of hyphal forms by cytology or direct microscopy.

3.      Skin ulcers, draining soft tissue lesions or fissure for which both microscopy and culture are required

Detection of antigen, cell wall constituents or nucleic acid

4.    Galactomannan antigen EIA (Platelia).

a)      a single plasma or serum sample positive for galactomannan

b)      a single BAL, pleural fluid or CSF sample positive for galactomannan

6. Glucan Assay is primarily applicable for aspergillosis and candidiasis and does not detect Cryptococcus species nor the Zygomycetes (Rhizopus spp., Mucor spp. Absidia spp.)

a single serum sample positive for beta-D-glucan

7. Polymerase Chain Reaction to detect nucleic acid

Until a PCR system is developed that has been externally validated, a positive PCR result for blood, tissue, or BAL fluid for the specific fungus studied will not be considered microbiological evidence of invasive fungal disease.

---

[1] Append identification at genus or species level from culture, if available.

[2] tissue and cells submitted for histopathology or cytopathology should be stained by Grocott-Gomorri methenamine silver stain or by periodic acid Schiff stains to facilitate inspection of fungal structures. Where possible, wet mounts of specimens from foci related to invasive fungal infectious disease should be stained with a fluorescent marker (e.g., calcofluor or Blancophor)

[3] Individual fungal invasive disease entities e.g. proven aspergillosis require culture and identification. Faiiling this the disease is designated as proven mould invasive fungal disease

[4] Other moulds can cause fungemia. However contamination should be excluded before assigning the diagnosis of proven invasive fungal disease

[5] Histoplasmosis, blastomycosis, coccidioidomycosis, and paracoccidioidomycosis, sporotrichosis and infection due to Penicillium marneffei

[6] the medical history must be established to distinguish between a primary and chronic pulmonary infection. Onset within 3 months defines a primary pulmonary infection.

[7] Histoplasma capsulatum variety capsulatum may resemble Candida glabrata or Leishmania in tissue but can be distinguished from them by the characteristic histologic features of granulomatous inflammation and staining by Grocott-Gomorri methenamine silver stain

[8] Testing should be performed only in laboratories where the assays have been validated; i.e., clinical correlations made with results and titers, and with data available on false positive and false negative rates with the test as performed in that laboratory.

[9] provided other plausible causes have been excluded

[10] symptoms not necessary if there is mycological evidence

diagnostic criteria for FAT EMBOLISM

Gurd’s criteria for the diagnosis of fat embolism syndrome


Major criteria
1 Axillary or subconjuctival petechia. This occurs transiently over 4–6 h in
50%–60% of patients
2 Hypoxemia (PaO2 <60mmHg; FiO2 <0.4)
3 Central nervous system depression disproportionate to hypoxemia, and
pulmonary edema
Minor criteria
1 Tachycardia (>110 beats/min)
2 Pyrexia (>38.5°)
3 Emboli in the retina on fundoscopic examination
4 Fat present in urine
5 Sudden unexplained drop in hematocrit or platelet values
6 Increasing erythrocyte sedimentation rate
7 Fat globules in the sputum
8 Symptoms within 72h of skeletal trauma
9 Shortness of breath
10 Altered mental status
11 Occasional long tract signs and posturing
12 Urinary incontinence

Criteria for the diagnosis of fat embolism syndrome according to Gurd and Wilson

Major criteria
1 Respiratory insufficiency
2 Cerebral involvement
3 Petechial rash
Minor criteria
1 Pyrexia (usually <39°C)
2 Tachycardia (>120 beats/min)
3 Retinal changes (fat or petechiae)
4 Jaundice
5 Renal changes (anuria or oliguria)
6 Anemia (a drop of more than 20% of the admission hemoglobin value)
7 Thrombocytopenia (a drop of >50% of the admission thrombocyte value)
8 High erythrocyte sedimentation rate (ESR >71mm/h)
9 Fat macroglobulinemia

At least two major symptoms
or signs or one major and four minor symptoms or
signs must be present to diagnose the syndrome

current concept in acute embolism ;FLOWCHART FOR DIAGNOSIS

reference new england journal of medicine 2010 june